Treatment of cardiac dysfunction

ABSTRACT

Modulation, preferably inhibition, of neurosignaling of a cardiac-related sympathetic nerve in the extracardiac intrathoracic neural circuit is effective in stabilizing cardiac electrical and/or mechanical function, thereby providing ways of treating or preventing cardiac dysfunction such as arrhythmias.

TECHNICAL FIELD

This invention relates to the treatment of cardiac dysfunction. Morespecifically, the invention relates to medical device and systems forthe treatment of cardiac dysfunction, and medical devices that deliverneuromodulatory therapy for such purposes.

BACKGROUND ART

Cardiac dysfunction refers to a pathological decline in cardiacperformance. Cardiac dysfunction refers to any cardiac disorders oraberrant conditions that are associated with or induced by the variouscardiomyopathies, cardiomyocyte hypertrophy, cardiac fibrosis, or othercardiac injuries. Specific examples of cardiac dysfunction includecardiac remodeling, cardiac hypertrophy, heart failure and cardiacarrhythmias. Cardiac dysfunction may be manifested through one or moreparameters or indicia including changes to stroke volume, ejectionfraction, end diastolic fraction, stroke work, arterial elastance, or anincrease in heart weight to body weight ratio.

Sudden cardiac death (SCD) is a leading cause of mortality worldwide,with approximately 300,000 people die suddenly of this cause every yearin the United States. Ventricular arrhythmias are the most common reasonfor SCD. There are many causes of ventricular arrhythmias and SCD,including genetic predisposition, drugs and acquired causes. Themajority of the patients with ventricular arrhythmias have apre-existing pathology.

The initiation and propagation of arrhythmia has been the focus ofintense research which is well documented in the literature. Cardiacinjury (e.g. infarction, focal inflammation) results in the formation ofa scar in the organ, leading to slowed and altered paths of electricalpropagation within the myocardium. This alters the integrativeregulation of the heart, creating a substrate for reentrant arrhythmias.The systemic effects of myocardium injury are characterized byactivation (e.g. afferent-mediated activation) of the neuroendocrinesystem, primarily sympatho-excitation in conjunction with withdrawal ofcentral parasympathetic tone, which provides short term benefits tomaintain cardiac output. The recovery from acute injury is characterizedby a state in which there is continued abnormal cardiacneurotransmission, such as afferent signaling (cardio-centricafferents). Mechanistically, such dysregulation reflects reactive andadaptive responses of the cardiac neural hierarchy leading to changes insensory transduction of the diseased myocardium and resulting in alteredneuronal network excitability. Such changes in neural processing aremanifest in intrathoracic neural circuit, spinal cord, brainstem andhigher centers of the CNS. The reorganization ultimately leads toconflict between central and peripheral aspects of the hierarchy. Thisaltered neural processing leads to maladaptive responses ultimatelyresulting in excessive sympatho-excitation and reduced parasympatheticdrive. These neural adaptations contribute to the evolution of pumpfailure and fatal arrhythmias.

Cardiac arrhythmias are routinely treated with medication, ablative anddevice therapy, e.g. implantable cardioverter defibrillator (ICD).Despite the current standard of care, there are many patients who areeither refractory to anti-arrhythmic medications, or new focal ablationscreated during catheterization procedures only offer temporary relief asthey themselves can become blocks for electrical wave propagation,therefore ventricular arrhythmias recur. ICDs have been associated witha poor prognosis [1,2].

The direct evidence showing impact of sympathetic signaling leading tocardiac arrhythmia came from a patient case study in whom antiarrhythmicand ICD therapy failed and the patient continued to suffer from highincidence of ICD shocks and skin burns as a result. This patient wastreated in the emergency room and the final controlling mechanism forarrhythmia management was initiation of thoracic epidural anesthesia(TEA). TEA resulted in complete cessation of shocks for up to 48 hours.This was further explored in patients with incessant ventriculartachycardia (VT) in whom the sympathetic paravertebral ganglia (T1-T4)were excised which led to reduction in the frequency of ICD shocks,suggesting that neural control of cardiac excitability may be exploitedfor arrhythmia treatment.

Attempts to treat ventricular arrhythmias include targeting elementswithin the cardiac sympathetic nervous system by electrical stimulationor transection. It was found that such an approach applied to theparavertebral chain can modulate autonomic imbalances and reducearrhythmias.

One surgical approach involves the resection (unilateral or bilateral)of stellate ganglion. Left and bilateral cardiac sympathetic denervationhave been shown to impart anti-arrhythmic effects in patients withrefractory ventricular arrhythmias or electrical storm [3]. Left cardiacsympathetic denervation (LCSD) has been shown to be effective inpreventing life-threatening ventricular arrhythmias [4,5,6]. It wasfound that LCSD raised the threshold for ventricular fibrillation (VF),which means that, independently of the underlying condition, VF is lesslikely to initiate. Historically, these surgical procedures remove allconnections from spinal cord neurons to adrenergic and other neuronalsomata in the thorax. Recently, these surgical approaches have beenmodified to surgically remove the caudal two-thirds of the stellateganglion along with their respective paravertebral chains down to the T4paravertebral ganglia. Although such surgical approaches have documentedanti-arrhythmic effects, lack of clear delineation and visualization ofcardiac specific neurons at the time of stellate decentralization leadsto adverse effects like Homer syndrome and anhydrosis [7], hyperalgesia[8]. Furthermore, these effects are irreversible.

There remains an urgent need for further and improved treatments ofcardiac dysfunction, in particular, those that confer minimal impact onbasal cardiac function.

SUMMARY OF THE INVENTION

The inventors found that reversible modulation (e.g. inhibition) of theneural activity of cardiac-related sympathetic nerves in theextracardiac intrathoracic neural circuit significantly decreasesarrhythmia risk in animal models. Thus, reversible and scalableinhibition of the neural activity of a cardiac-related sympathetic nervein the extracardiac intrathoracic neural circuit is capable of treatingor preventing cardiac dysfunction.

More specifically, the inventors identified that inhibiting thesympathetic projections at a nexus intervention point in theextracardiac intrathoracic neural circuit (e.g. at the ansae subclaviaor at the T1-T2 paravertebral ganglia) is effective in stabilizingcardiac electrical and/or mechanical function. The nerve conduction inthe sympathetic chain ganglia (or in the case of ansae subclavian withinaxons of passage) can be reversibly inhibited using electrical signalsto create a finite region of axons through which action potentialscannot pass. This neural modulation is scalable and includes afferentand efferent nerve projections. This overrides integrated centralcontrol of sympathetic activity, decreasing ventricular excitabilityleading to a reduction in arrhythmia risk. One particular advantage isthat there is minimal effect on the basal cardiac function, but withefficacy on evoked neural responses. Furthermore, upon cessation ofelectrical signals, the inhibition ceases and multi-level cardiac reflexcontrol resumes. These advantages are demonstrated in the examplesbelow.

Thus, the invention provides a method of treating or preventing cardiacdysfunction in a subject by reversibly inhibiting neural activity of acardiac-related sympathetic nerve in the extracardiac intrathoracicneural circuit. For example, the invention provides a method of treatingventricular arrhythmias post-myocardial infarction. A preferred way ofreversibly inhibiting the cardiac-related sympathetic nerve activityuses a device or system which applies a signal to the cardiac-relatedsympathetic nerve in the extracardiac intrathoracic neural circuit.

The invention also provides a method of treating or preventing cardiacdysfunction in a subject, comprising applying a signal to acardiac-related sympathetic nerve in the extracardiac intrathoracicneural circuit in the subject to reversibly inhibit the neural activityof the cardiac-related sympathetic nerve. In some embodiments, themethod is for treating ventricular arrhythmias post-myocardialinfarction.

The invention provides an implantable device or system according to theinvention comprising at least one transducer, preferably an electrode,suitable for placement on or around a cardiac-related sympathetic nervein the extracardiac intrathoracic neural circuit, and a signal generatorfor generating a signal to be applied to the cardiac-related sympatheticnerve via the at least one transducer such that the signal reversiblyinhibits the neural activity of the cardiac-related sympathetic nerve toproduce a physiological response in the subject. The physiologicalresponse may be a decrease in a chronotropic, a dromotropic, alusitropic and/or an inotropic evoked response. In some embodiments, thecardiac-related sympathetic nerve is an efferent nerve. In someembodiments, the signal is KHFAC, CBDCC, or a hybrid thereof.

The invention also provides a method of treating or preventing cardiacdysfunction in a subject, comprising: (i) implanting in the subject adevice or system of the invention; (ii) positioning the transducer ofthe device or system in signaling contact with a cardiac-relatedsympathetic nerve in the extracardiac intrathoracic neural circuit inthe subject; and optionally (iii) activating the device or system. Insome embodiments, the method is for treating ventricular arrhythmiaspost-myocardial infarction.

Similarly, the invention provides a method of reversibly inhibitingneural activity in a subject's cardiac-related sympathetic nerve in theextracardiac intrathoracic neural circuit, comprising: (i) implanting inthe subject a device or system of the invention; positioning thetransducer in signaling contact with the subject's cardiac-relatedsympathetic nerve; and optionally (iii) activating the device or system.

The invention also provides a method of implanting a device or a systemof the invention in a subject, comprising: positioning a transducer ofthe device or system in signaling contact with the subject'scardiac-related sympathetic nerve in the extracardiac intrathoracicneural circuit.

The invention also provides a device or a system of the invention,wherein the device or system is attached to a cardiac-relatedsympathetic nerve in the extracardiac intrathoracic neural circuit.

The invention further provides a neuromodulatory (e.g. neuroinhibitory)electrical waveform for use in treating or preventing cardiacdysfunction in a subject, wherein the waveform is comprised of aplurality of repeating cycles of DC pulses, each cycle comprising aplurality of DC pulses applied sequentially at different locations onthe subject's cardiac-related sympathetic nerve in the extracardiacintrathoracic neural circuit such that when applied to a subject'scardiac-related sympathetic nerve in the extracardiac intrathoracicneural circuit, the waveform reversibly inhibits neural activity in thecardiac-related sympathetic nerve in the extracardiac intrathoracicneural circuit. In some embodiments, the neuromodulatory electricalwaveform is for use in treating ventricular arrhythmias post-myocardialinfarction.

The invention further provides a plurality of neuromodulatory (e.g.neuroinhibitory) electrical waveforms for use in treating or preventingcardiac dysfunction in a subject, wherein each waveform is comprised ofa plurality of charge-balanced DC pulses, the plurality of waveformsapplied sequentially at a corresponding plurality of locations on thesubject's cardiac-related sympathetic nerve in the extracardiacintrathoracic neural circuit such that when applied to a subject'scardiac-related sympathetic nerve in the extracardiac intrathoracicneural circuit, the plurality of waveforms reversibly inhibit neuralactivity in the cardiac-related sympathetic nerve in the extracardiacintrathoracic neural circuit. In some embodiments, the plurality ofneuromodulatory electrical waveforms are for use in treating ventriculararrhythmias post-myocardial infarction.

Before effecting modulation (e.g. becoming inhibitory), electricalsignaling can be preceded by a short period in which the nerve isinstead stimulated (an “onset response” or “onset effect”). Various waysof avoiding an onset response are available. In certain embodiments, anonset response as a result of the signal being applied can be avoided ifthe signal does not have a frequency of 20 kHz or lower, for example1-20 kHz, or 1-10 kHz. Frequency- and amplitude-transitioned waveformsto mitigate onset responses in high-frequency nerve blocking aredescribed by Gerges et al. [9]. Amplitude ramping can also be used, asdiscussed by Bhadra et al. [10], or a combination of KHFAC with chargebalanced direct current waveforms can be used [11]. A combination ofKHFAC and infra-red laser light (‘ACIR’) has also been used to avoidonset responses [12].

In certain embodiments, the waveform comprises a DC ramp and a KHFACwaveform that commences during the DC ramp. In particular embodiments,the waveform comprises a DC ramp followed by a plateau andcharge-balancing, followed by a first AC waveform, wherein the amplitudeof the first AC waveform increases during the period in which the firstAC waveform is applied, followed by a second AC waveform having a loweramplitude and/or lower frequency than the first AC waveform. In certainsuch embodiments, the DC ramp, first AC waveform and second AC waveformare applied substantially sequentially.

In certain embodiments, the waveform comprises a kilohertz frequencyalternating current (KHFAC) waveform, a charge-balanced direct currentcarousel (CBDCC) waveform, or a hybrid thereof.

Of course, associated devices configured to apply such signals, andmethod of applying such signals are also possible, as describedelsewhere herein.

The invention also provides the use of a neuromodulatory (e.g.neuroinhibitory) device or system for treating or preventing cardiacdysfunction in a subject, by reversibly inhibiting neural activity inthe subject's cardiac-related sympathetic nerve in the extracardiacintrathoracic neural circuit. In some embodiments, the use is fortreating ventricular arrhythmias post-myocardial infarction.

The invention also provides a charged particle for use in a method oftreating or preventing cardiac dysfunction, wherein the charged particlecauses reversible depolarization or hyperpolarization of the nervemembrane, such that an action potential does not propagate through themodified nerve. In some embodiments, the use is in a method of treatingventricular arrhythmias post-myocardial infarction.

The invention also provides an electrical waveform for use in a methodof treating or preventing cardiac dysfunction, wherein a chargedparticle elicited by the electrical waveform causes reversibledepolarization or hyperpolarization of the nerve membrane, such that anaction potential does not propagate through the modified nerve. In someembodiments, the plurality of electrical waveforms are for use intreating ventricular arrhythmias post-myocardial infarction.

The invention also provides a modified cardiac-related sympathetic nervein the extracardiac intrathoracic neural circuit to which a transducerof the system or device of the invention is attached. The transducer isin signaling contact with the nerve and so the nerve can bedistinguished from the nerve in its natural state. Furthermore, thenerve is located in a patient who suffers from, or is at risk of,cardiac arrhythmia.

The invention also provides a modified cardiac-related sympathetic nervein the extracardiac intrathoracic neural circuit, wherein the neuralactivity is reversibly inhibited by applying a signal to thecardiac-related sympathetic nerve in the extracardiac intrathoracicneural circuit. In some embodiments, the signal is KHFAC, CBDCC, or ahybrid thereof.

The invention also provides a modified cardiac-related sympathetic nervein the extracardiac intrathoracic neural circuit, wherein the nervemembrane is reversibly deploarized or hyperpolarized by an electricfield, such that an action potential does not propagate through themodified nerve. In some embodiments, the electrical field is caused byapplying a signal to the nerve, where the signal is optionally KHFAC, aCBDCC, or a hybrid thereof.

The invention also provides a modified cardiac-related sympathetic nervein the extracardiac intrathoracic neural circuit bounded by a nervemembrane, comprising a distribution of potassium and sodium ions movableacross the nerve membrane to alter the electrical membrane potential ofthe nerve so as to propagate an action potential along the nerve in anormal state; wherein at least a portion of the nerve is subject to theapplication of a temporary external electrical field which modifies theconcentration of potassium and sodium ions within the nerve, causingdepolarization or hyperpolarization of the nerve membrane, therebytemporarily blocking the propagation of the action potential across thatportion in a disrupted state, wherein the nerve returns to its normalstate once the external electrical field is removed. In someembodiments, the electrical field is caused by applying a signal to thenerve, where the signal is optionally KHFAC, a CBDCC, or a hybridthereof.

The invention also provides a modified cardiac-related sympathetic nervein the extracardiac intrathoracic neural circuit obtainable byreversibly inhibiting neural activity of the cardiac-related sympatheticnerve according to a method of the invention.

The invention also provides a method of modifying the cardiac-relatedsympathetic nerve in the extracardiac intrathoracic neural circuit'sactivity, comprising a step of applying a signal to the cardiac-relatedsympathetic nerve in the extracardiac intrathoracic neural circuit inorder to reversibly inhibit the neural activity of the cardiacsympathetic nerve in a subject. Preferably the method does not involve amethod for treatment of the human or animal body by surgery. The subjectalready carries a device or system of the invention which is insignaling contact with a cardiac-related sympathetic nerve in theextracardiac intrathoracic neural circuit.

The invention also provides a method of controlling a device or systemof the invention which is in signaling contact with a cardiac-relatedsympathetic nerve in the extracardiac intrathoracic neural circuit,comprising a step of sending, preferably externally sending, controlinstructions to the device or system, in response to which the device orsystem applies a signal to the cardiac-related sympathetic nerve in theextracardiac intrathoracic neural circuit.

DETAILED DESCRIPTION OF THE INVENTION

Cardiac-Related Sympathetic Nerve in the Extracardiac IntrathoracicNeural Circuits

The invention involves modulation (e.g. inhibition) of the neuralactivity of a cardiac-related sympathetic nerve in the extracardiacintrathoracic neural circuit. By modulating the sympathetic neuralsignals to the heart, it is possible to achieve therapeutic effects. Forexample, inhibiting the sympathetic neural signals to the heart maydecrease the chronotropic, dromotropic, lusitropic and/or inotropicevoked responses of the heart, leading to stabilization of the cardiacelectrical and/or mechanical function (e.g. restoring heart rate, heartrhythm, contractility and blood pressure towards normal baselinelevels), thereby decreasing the risk of cardiac dysfunction.

The autonomic nervous system exerts a strong influence on cardiacfunction [13]. The major sources of cardiac innervations are from thebrainstem/vagus and the spinal cord/intrathoracic sympathetic ganglia.These extracardiac parasympathetic and sympathetic nerves carry afferentand efferent information, and communicate and control cardiac functionvia several ganglia on the heart. Within these intra-cardiac ganglia,there are many intra-cardiac neurons that intercommunicate and processinformation, such as incoming efferent information, and preferably actto both filter and augment the afferent signals, forming a tighthierarchy of neural circuits. The neural circuits also form interactingfeedback loops to provide physiological stability for maintaining normalrhythm and life-sustaining circulation. These nested feedback loopsensure that there is fine-tuned regulation of efferent (sympathetic andparasympathetic cardiomotor) neural signals to the heart in normal andstressed hearts. These neural elements comprise the intrinsic cardiacnervous system which interact with extracardiac ganglia and the centralelements of the nervous system to dynamically control heart function.

Cardiac-related sympathetic efferent preganglionic neurons originate inthe intermediolateral column of the spinal cord and project their axonsvia the C7-T6 rami into the paravertebral chain (e.g. [7,14,15,16,17,18]). From there, the cardiac-related preganglionic fibersproject to sympathetic efferent postganglionic neuronal somata containedin the superior cervical, middle cervical, mediastinal ganglia andstellate ganglia. The primary interconnection between the stellate,middle cervical and the mediastinal ganglia is via the dorsal andventral ansae subclavia [19]. FIG. 1 provides a schematic diagram of thegross anatomic arrangement of these nerves.

The invention modulates (e.g. inhibits) the neural activity of acardiac-related sympathetic nerve in the extracardiac intrathoracicneural circuit. This modulation (e.g. inhibition) may involve efferent,afferent, or both afferent and efferent, neurons. This modulation (e.g.inhibition) may involve fibers of passage or synaptic processing withintrathoracic ganglia.

Within the extracardiac intrathoracic neural circuit, thecardiac-related sympathetic nerve may be modulated (e.g. inhibited) atthe sympathetic paravertebral chain, e.g. between the lower cervical(e.g. inferior cervical ganglia) and upper thoracic paravertebral chain(e.g. T1-T4 ganglia).

A cardiac-related sympathetic nerve may be modulated (e.g. inhibited) ator caudal to the middle cervical ganglion. Elements along and arisingfrom the paravertebral chain that are caudal to the middle cervicalganglion include the ansae subclavia and the inferior cervical ganglion.

The inferior cervical ganglion is fused with the first thoracic ganglion(T1) to form a single structure called the stellate ganglion in around80% of the human population. Thus, the cardiac-related sympathetic nervemay be modulated (e.g. inhibited) at or caudal to the inferior cervicalganglion or the stellate ganglion in the paravertebral chain.

The ansae subclavia are nerve cords that surround the subclavian artery,and form the primary interconnection between the stellate, middlecervical and the mediastinal ganglia [19]. The dorsal ansae subclaviaarise as a craniomedial extension of the stellate ganglion and areusually shorter and thicker than the ventral ansae, which loopanteriorly around the subclavian artery. There is anatomicalheterogeneity in that each individual may have one or more ansaesubclavia. For example, the ansae subclavia can exist as single ormultiple nerve cords, and the right side tends to have more nerve cordsin total than the left. There are variations according to the origin andtermination of the loop, for example, in some individuals no distinctdorsal ansae can be seen because the stellate and the inferior-mostmiddle cervical ganglia form a large swelling. The invention may beapplied to one or more of the ansae subclavia.

The invention preferably modulates (e.g. inhibits) at or caudal to theansae subclavia. This is because the ansae subclavia represents thelowest nexus point in the cardiac nervous system hierarchy forsympathetic projection to the heart that is amenable to transducerattachment. From the ansae subclavia, the cardiac-related sympatheticnerves become more diffused so it is practically more difficult totarget them. Inhibiting neural activity at the ansae subclavia isparticularly effective in affecting cardiac electrical and/or mechanicalfunction, including rhythm and contractility, as demonstrated in theexamples below. The site of modulation (e.g. inhibition) may be at thejunction between the dorsal and ventral rami of the ansae subclaviaadjacent to the stellate ganglion.

Since the invention involves reversibly inhibiting a cardiac-relatedsympathetic nerve, the risks of complications associated with stellateganglion block [20], e.g. Homer's syndrome, intra-arterial orintravenous injection, difficulty swallowing, vocal cord paralysis,epidural spread of local anaesthetic and pneumothorax, will beminimized. Blocking at the inferior cervical ganglion is undesirablebecause it can inhibit pain detection.

A cardiac-related sympathetic nerve may be modulated (e.g. inhibited) ator cranial to the T4 ganglion along the paravertebral chain. Preferably,the inhibition is at or cranial to the T3 ganglion along theparavertebral chain, which includes the ansae subclavia. The inhibitionmay be at or cranial to the T2 ganglion along the paravertebral chain.Preserving the T3 element and the more caudal elements of theparavertebral chain is useful because they are associated with sensoryand sympathetic motor control of upper limb, neck and thoracic wall, sothe risks for upper limb and thoracic wall pain syndromes and anhydrosiscan be minimized. The invention therefore preferably inhibits neuralactivity of a cardiac-related sympathetic nerve at a site along theparavertebral chain that is cranial to the T3 ganglion. The inventionpreferably does not inhibit the neural activity of a cardiac-relatedsympathetic nerve at the T3 ganglion.

The invention may modulate (e.g. inhibit) a cardiac-related sympatheticnerve at any site along the paravertebral chain (which includes theansae subclavia) between the middle cervical and T4 ganglia, between themiddle cervical and T3 ganglia, or between the middle cervical and T2ganglia. The inhibition may be at any site along the paravertebral chainbetween the inferior cervical and T4 ganglia, between the inferiorcervical and T3 ganglia, or between the inferior cervical and T2ganglia. The inhibition may be at any site along the paravertebral chainbetween the ansae subclavia and T4 ganglion, between the ansae subclaviaand T3 ganglion, or between the ansae subclavia and T2 ganglion. Theinhibition may be at any site along the paravertebral chain between thestellate and T4 ganglia, between the stellate and T3 ganglia, or betweenthe stellate and T2 ganglia. The inhibition may be at any site along theparavertebral chain between the T1 and T4 ganglia, between the T1 and T3ganglia, or between the T1 and T2 ganglia.

Preferably, the cardiac-related sympathetic nerve is inhibited at a sitealong the paravertebral chain between the stellate ganglion and the T4ganglion.

The invention preferably modulates (e.g. inhibits) neural activity of acardiac-related sympathetic nerve between the T2 ganglion and theganglion cranial to T2, which may be the stellate ganglion or the T1ganglion. The specific anatomical structure that is inhibited woulddepend on the anatomical arrangement of the individual. This region hasbeen shown to be particularly effective for inhibiting neural activity,as demonstrated in the examples below. This region is amenable forelectrodes attachment. Also, inhibition of neural activity in thisregion minimizes adverse or off-target effects, as explained above.

Ideally, the cardiac-related sympathetic nerve to be inhibited isamenable to transducer (e.g. electrode) attachment. For example, thenerve is accessible for an electrode attachment, and is not obstructedby ganglia, branching nerves, other nerves or blood vessels. Forexample, Study 4 shows that the region at the paravertebral ganglionbetween the T1 and T2 levels is amenable to electrode attachment, e.g.DC carousel (DCC) electrodes. As well as being accessible, the T1-T4region tends to be consistent from patient to patient, thus facilitatingthis site for general use. The T1-T4 and T1-T2 regions have beenpreviously used as a point of intervention [21].

Plasticity exists for cardiac-related sympathetic nerves in theextracardiac intrathoracic neural circuits. For example, neuralremodeling including neuron cell body hypertrophy, increased fibrosis,and increased synaptic density have been shown to occur in the left andin both stellate ganglia in patients with cardiomyopathy and in ananimal model of myocardial infarction [22,23]. Thus, the exact site forinhibiting neural activity may vary from human to human, but isnonetheless within the extracardiac intrathoracic neural circuit asexplained above.

Typically, the invention involves modulation (e.g. inhibition) of acardiac-related sympathetic nerve in the extracardiac intrathoracicneural circuit that is located in a bundle of nerves, e.g. in thesympathetic paravertebral chain or in the ansae subclavia. The inventionmay therefore involve inhibition of one or more cardiac-relatedsympathetic nerves.

The sympathetic paravertebral chain lies on either side of the vertebralcolumn and essentially extends along its length. Thus, when theinvention refers to a cardiac-related sympathetic nerve in thesympathetic paravertebral chain and/or its elements (e.g. ansaesubclavia), it may be referring to the right and/or left sympatheticparavertebral chain and/or its elements (e.g. ansae subclavia). Hence,the invention may refer to modulation (e.g. inhibition) ofcardiac-related sympathetic nerve bilaterally at the sympatheticparavertebral chain and/or its elements (e.g. ansae subclavia). Theinvention may refer to inhibition of a cardiac-related sympathetic nerveunilaterally at the sympathetic paravertebral chain and/or its elements(e.g. ansae subclavia).

Inhibition of neural activity of one instead of both sides is sufficientfor achieving beneficial physiological effects. This is useful for theinvention because it minimizes the interruption of neural activity,thereby minimizes any adverse off-target effects. The examples belowshows that neural block of the right T1-T2 paravertebral chain areeffective in stabilizing cardiac electrical and/or mechanical function.This is consistent with previous animal studies showing that sectioningeither the right or the left ansae subclavia abolished all cardiaceffects produced by stimulating that ganglion [24]. Thus, the inventioninhibits a cardiac-related sympathetic nerve at either the right or theleft sympathetic paravertebral chain and/or its elements (e.g. ansaesubclavia). For example, the invention may inhibit a cardiac-relatedsympathetic nerve at the right and/or the left ansae subclavia. Theinvention may inhibit a cardiac-related sympathetic nerve at the rightand/or the left T1-T2 paravertebral chain.

For example, the invention may involve modulation (e.g. inhibition) of acardiac-related sympathetic nerve at one or more sites selected from thegroup consisting of: mediastinal ganglion, right middle cervicalganglion, left middle cervical ganglion, right ansae subclavia, leftansae subclavia, right stellate ganglion, left stellate ganglion, rightparavertebral chain between T1-T6 ganglia, left paravertebral chainbetween T1-T6 ganglia, right paravertebral chain between T1-T4 ganglia,left paravertebral chain between T1-T4 ganglia, right paravertebralchain between T1-T2 ganglia and left paravertebral chain between T1-T2ganglia.

The cardiac-related sympathetic nerve to be modulated (e.g. inhibited)is in either an afferent or an efferent neural circuit. When theinvention refers to inhibition of more than one cardiac-relatedsympathetic nerves, the cardiac-related sympathetic nerves may be in:(a) an afferent neural circuit, (b) an efferent neural circuit, or (c)both afferent and efferent neural circuits.

Where the invention refers to a modified cardiac-related sympatheticnerve in the extracardiac intrathoracic neural circuit, this nerve isideally present in situ in a subject.

Inhibition of Neural Activity

According to the invention, inhibition results in neural activity in atleast part of the cardiac-related sympathetic nerve in the extracardiacintrathoracic neural circuit being reduced compared to baseline neuralactivity in that part of the nerve. This reduction in activity can beacross the whole nerve, in which case neural activity is reduced acrossthe whole nerve.

As used herein, “neural activity” of a nerve means the signalingactivity of the nerve, for example the amplitude, frequency and/orpattern of action potentials in the nerve. The term “pattern”, as usedherein in the context of action potentials in the nerve, is intended toinclude one or more of: local field potential(s), compound actionpotential(s), aggregate action potential(s), and also magnitudes,frequencies, areas under the curve and other patterns of actionpotentials in the nerve or sub-groups (e.g. fascicules) of neuronstherein.

In some cases, the inhibition of neural activity may be a block ofneural activity i.e. action potentials are blocked from travellingbeyond the point of the block in at least a part of the cardiac-relatedsympathetic nerve in the extracardiac intrathoracic neural circuit. Ablock on neural activity is thus understood to be blocking neuralactivity from continuing past the point of the block. That is, when theblock is applied, action potentials may travel along the nerve or subsetof nerve fibers to the point of the block, but not beyond the point ofthe block. Thus, the nerve or subset of nerve fibers at the point ofblock is modified in that the nerve membrane is reversibly depolarizedor hyperpolarized by an electric field, such that an action potentialdoes not propagate through the modified nerve. Hence, the nerve or thesubset or nerve fibers at the point of the block is modified in that ithas lost its capacity to propagate action potentials, whereas theportions of the nerve or the subset of nerve fibers before and after thepoint of block have the capacity to propagate action potentials.

When an electrical signal is used with the invention, the block is basedon the influence of electrical currents (e.g. charged particles, whichmay be one or more electrons in an electrode attached to the nerve, orone or more ions outside the nerve or within the nerve, for instance) onthe distribution of ions across the nerve membrane.

At any point along the axon, a functioning nerve will have adistribution of potassium and sodium ions across the nerve membrane. Thedistribution at one point along the axon determines the electricalmembrane potential of the axon at that point, which in turn influencesthe distribution of potassium and sodium ions at an adjacent point,which in turn determines the electrical membrane potential of the axonat that point, and so on. This is a nerve operating in is normal state,wherein action potentials propagate from point to adjacent point alongthe axon, and which can be observed using conventional experimentation.One way of characterizing a block of neural activity is a distributionof potassium and sodium ions at one or more points in the axon which iscreated not by virtue of the electrical membrane potential at adjacent apoint or points of the nerve as a result of a propagating actionpotential, but by virtue of the application of a temporary externalelectrical field. The temporary external electrical field artificiallymodifies the distribution of potassium and sodium ions within a point inthe nerve, causing depolarization or hyperpolarization of the nervemembrane that would not otherwise occur. The depolarization orhyperpolarization of the nerve membrane caused by the temporary externalelectrical field blocks the propagation of an action potential acrossthat point, because the action potential is unable to influence thedistribution of potassium and sodium ions, which is instead governed bythe temporary external electrical field. This is a nerve operating in adisrupted state, which can be observed by a distribution of potassiumand sodium ions at a point in the axon (the point which has beenblocked) that has an electrical membrane potential that is notinfluenced or determined by a the electrical membrane potential of anadjacent point.

Block of neural activity encompasses full block of neural activity inthe nerve, i.e. there is no neural activity in the whole nerve.

Blocking may be a partial block. Partial block may be such that thetotal signaling of a subset of nerve fibers of the nerve is partiallyreduced compared to baseline neural activity in that subset of fibers ofthe nerve. For example a reduction in neural activity of 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 40%, 50%, 60%, 70%, 80%, 90% or 95%, orblocking of neural activity in a subset of nerve fibers of the nerve.The neural activity may be measured by methods known in the art, forexample, by the number of action potentials which propagate through theaxon and/or the amplitude of the local field potential reflecting thesummed activity of the action potentials.

The invention may selectively block nerve fibers of various sizes withina nerve. Larger nerve fibers tend to have a lower threshold for blockingthan smaller nerve fibers. Thus, for example, increasing signalamplitude (e.g. increasing amplitude of an electric signal) may generateblock of the smaller fibers.

Block of neural activity as described herein should not be confused withthe clinical condition of “heart block”, which typically occurs if thetransmission of the pulse between the sinoatrial (SA) node, theatrioventricular (AV) node and the ventricles is interrupted.

Modulation (e.g. inhibition) of neural activity may be an alteration inthe pattern of action potentials. It will be appreciated that thepattern of action potentials can be modulated without necessarilychanging the overall frequency or amplitude. For example, modulation(e.g. inhibition) of the neural activity may be such that the pattern ofaction potentials is altered to more closely resemble a healthy staterather than a disease state.

Modulation (e.g. inhibition) of neural activity may comprise alteringthe neural activity in various other ways, for example increasing ordecreasing a particular part of the neural activity and/or stimulatingnew elements of activity, for example: in particular intervals of time,in particular frequency bands, according to particular patterns and soforth.

One advantage of the invention is that modulation (e.g. inhibition) ofthe neural activity is reversible. Hence, the modulation (e.g.inhibition) of neural activity is not permanent. For example, uponcessation of inhibition, neural activity in the nerve returnssubstantially towards baseline neural activity within 1-60 seconds, orwithin 1-60 minutes, or within 1-24 hours (e.g. within 1-12 hours, 1-6hours, 1-4 hours, 1-2 hours), or within 1-7 days (e.g. 1-4 days, 1-2days). In some instances of reversible inhibition, the neural activityreturns substantially fully to baseline neural activity. That is, theneural activity following cessation of inhibition is substantially thesame as the neural activity prior to inhibition (e.g. prior to a signalbeing applied). Hence, the nerve or the portion of the nerve hasregained its capacity to propagate action potentials.

In other embodiments, modulation (e.g. inhibition) of the neuralactivity may be substantially persistent. As used herein, “persistent”is taken to mean that the modulated (e.g. inhibited) neural activity hasa prolonged effect. For example, upon cessation of inhibition, neuralactivity in the nerve remains substantially the same as when inhibitionwas occurring—i.e. the neural activity during and following inhibitionis substantially the same. Reversible inhibition is preferred.

Inhibition of the neural activity may be (at least partially)corrective. As used herein, “corrective” is taken to mean that theinhibited neural activity alters the neural activity towards the patternof neural activity in a healthy individual, and this is called axonalmodulation therapy. That is, upon cessation of inhibition, neuralactivity in the nerve more closely resembles (ideally, substantiallyfully resembles) the pattern of action potentials in the cardiac-relatedsympathetic nerve in the extracardiac intrathoracic neural circuitobserved in a healthy subject than prior to inhibition. Such correctiveinhibition can be any inhibition as defined herein. For example,inhibition may result in a block on neural activity, and upon cessationof inhibition the pattern of action potentials in the nerve resemblesthe pattern of action potentials observed in a healthy subject. By wayof further example, inhibition may result in neural activity resemblingthe pattern of action potentials observed in a healthy subject and, uponcessation of inhibition, the pattern of action potentials in the nerveremains the pattern of action potentials observed in a healthy subject.

By way of further example, inhibition may result in modulation such thatcardiac-related sympathetic nerve in the extracardiac intrathoracicneural circuit neural activity resembles the pattern of actionpotentials observed in a healthy subject, and upon cessation of thesignal, the pattern of action potentials in the nerve resembles thepattern of action potentials observed in a healthy subject. It ishypothesized that such a corrective effect is the result of a positivefeedback loop—that is, the underlying disease state is treated as resultof the claimed methods, and therefore the multi-modal sensory signalsalong the cardiac-related sympathetic nerve in the extracardiacintrathoracic neural circuit are not abnormal, and therefore the diseasestate is not perpetuated by the abnormal cardiac-related sympatheticnerve in the extracardiac intrathoracic neural circuit neural activity.

Treatment or Prevention of Cardiac Dysfunction

The invention is useful in treatment or prevention of cardiacdysfunction.

The invention is useful for treating or preventing any cardiac conditionwhere the pathology is driven by sympatho-excitation. Cardiac rate,contractility, and excitability are known to be modulated by centrallymediated reflex pathways. The heart rate, spread of electrical activityon the heart and force of contraction is increased when the sympatheticnervous system is stimulated, and is decreased when the sympatheticnervous system is inhibited. This may also be accomplished when theparasympathetic nervous system is stimulated. Increased sympathetic toneis associated with various cardiac conditions, e.g. heart failure,myocardial infarction, hypertension and cardiac arrhythmias.

Heart failure is a condition caused by the heart failing to pump enoughblood around the body to meet the demands of peripheral tissues. Heartfailure may present itself as congestive heart failure (CHF) due to theaccompanying venous and pulmonary congestion. Heart failure can be dueto a variety of etiologies such as ischemic heart disease. Cardiacdecompensation is typically marked by dyspnea (difficulty breathing),venous engorgement and edema, and each decompensation event can causefurther long term deterioration of the heart function. Heart failurepatients have reduced autonomic balance, typically with a sympatheticoverdrive, which is associated with left ventricular dysfunction andincreased mortality.

Myocardial infarction occurs when myocardial ischemia, a diminishedblood supply to the heart, exceeds a critical threshold and results inirreversible myocardial cell damage or death.

The invention may relate to treating or preventing cardiac arrhythmia,also called cardiac dysrhythmia (or simply irregular heart beat), whichrefers to a group of conditions in which there is abnormal electricalactivity in the heart. Some arrhythmias are life-threatening medicalemergencies that can result in cardiac arrest and sudden death. Othercause symptoms such as an abnormal awareness of heart beat. Others maynot be associated with any symptoms at all but predispose towardpotentially life-threatening stroke, embolus or cardiac arrest. Cardiacarrhythmia can be classified by rate (physiological, tachycardia orbradycardia), mechanism (automaticity, re-entry or fibrillation) or bysite of origin (ventricular or supraventricular).

Preferably, the invention relates to treating or preventing ventriculararrhythmia, e.g. ventricular tachycardia (VT) and ventricularfibrillation (VF). Ventricular arrhythmias are characterized by adisruption in the normal excitation-contraction rhythm of heart. Inparticular, VT and VF are characterized by abnormally rapid,asynchronous contraction of the ventricles. As such, the heart is unableto adequately pump oxygenated blood to the systemic circulation. If nottreated immediately, ventricular arrhythmias can lead to additionaltissue damage or patient death. These potentially life threateningevents are characterized by, among other things, an increase intransient calcium currents and an elevation in diastolic calciumconcentration in cardiac tissue, lengthening of the cardiac actionpotential, a drop in blood pressure and ischemia (lack of adequate bloodflow to the heart). These changes can potentially affect the return ofspontaneous circulation, hemodynamics, refibrillation and resuscitationsuccess.

The inventors found that electric nerve block application duringaberrant cardiac sympathetic stimulation is capable of stabilizingcardiac electrical and/or mechanical function. For example, Study 3shows that when DC was delivered to the T1-T2 region during T3stimulation, the increase in the chronotropic, dromotropic and inotropicfunctions in response to T3 stimulation was reduced during the period ofDC delivery. Thus, electric nerve block (e.g. DC block) is effective intreating cardiac dysfunction, i.e. the electric nerve block can be usedin a reactive manner. The invention can be configured as a closed-loopwhere the control of block is engaged automatically via one or morephysiological sensors (described further below).

The inventors also found that electric nerve block application at theonset of aberrant cardiac sympathetic stimulation is capable ofpreventing cardiac dysfunction. For example, Study 3 shows that when DCwas delivered at the onset of T3 stimulation, the increase in thechronotropic and inotropic functions in response to T3 stimulation wasnot achieved until after DC delivery was removed. Interestingly, thepercentages block of inotropic and chronotropic responses were highlyeffective for DC pre-emptive use, with at least 80% block for bothinotropic and chronotropic responses. Thus, electric nerve block (e.g.DC block) is effective in preventing cardiac dysfunction, i.e. theelectric nerve block can be used in a pre-emptive manner. Thepre-emptive use can be configured as: (i) a closed-loop where thecontrol of block is automatically via one or more physiological sensors(described further below); or (ii) an open-loop where the control ofblock is through a switch.

Assessing Cardiac Dysfunction

The invention may also involve detecting one or more signals from thesubject indicative of cardiac function. This may be done before, duringand/or after modulation (e.g. inhibition) of neural activity in acardiac-related sympathetic nerve in the extra-cardiac intrathoracicneural circuit. The signal may be a physiological response indicated byassessing a biomarker indicative of cardiac dysfunction.

Thus the invention may involve assessing a biomarker indicative ofcardiac dysfunction, which may be organ-based or neuro-based. Anorgan-based biomarker may be any measurable physiological parameter ofthe heart. For example, a physiological parameter may be one or more ofthe group consisting of: a chronotropic response, a dromotropicresponse, a lusitropic response and an inotropic response. Any of theseparameters may be indicated by measuring the heart rate, heart rhythmand heart electro-mechanical coupling (e.g. ventricular pressure,ventricular contractility, activation-recovery interval, effectiverefractory period, stroke volume, ejection fraction, end diastolicfraction, stroke work, arterial elastance).

Chronotropic responses refer to changes in the heart rate and/or rhythm.These effects may be indicated using known techniques in the art, suchas by electrocardigraphy, e.g. using the RR-interval.

Dromotropic responses refer to changes to the conduction speed in theatrioventricular (AV) node. These effects may be indicated using knowntechniques in the art, such as by electrocardigraphy, e.g. using thePR-interval which would indicate the electrical spread across the atriato the AV-node.

Lusitropic responses refer to the changes in the rate of myocardialrelaxation. These effects may be indicated using known techniques in theart, such as by measuring the rate of pressure change in the ventricle(e.g. dP/dT).

Inotropic responses refer to the strength of contraction of heart muscle(i.e. myocardial contractility). These effects may be indicated usingknown techniques in the art, such as by measuring the rate of pressurechange in the ventricle (e.g. dP/dT). Respiration parameters may also beuseful. They can be derived from, for example, a minute ventilationsignal and a fluid index can be derived from transthoracic impedance.For example decreasing thoracic impedance reflects increased fluidbuildup in lungs, and indicates a progression of heart failure.Respiration can significantly vary minute ventilation. The transthoracicimpedance can be totaled or averaged to provide an indication of fluidbuildup.

Heart Rate Variability (HRV) a technique useful for assess autonomicbalance. HRV relates to the regulation of the sinoatrial node, thenatural pacemaker of the heart by the sympathetic and parasympatheticbranches of the autonomic nervous system. An HRV assessment is based onthe assumption that the beat-to-beat fluctuations in the rhythm of theheart provide us with an indirect measure of heart health, as defined bythe degree of balance in sympathetic and parasympathetic nerve activity.

The invention may involve assessing the heart rate by methods known inthe art, for example, with a stethoscope or by feeling peripheralpulses. These methods cannot usually diagnose specific arrhythmias butcan give a general indication of the heart rate and whether it isregular or irregular. Not all of the electrical impulses of the heartproduce audible or palpable beats; in many cardiac arrhythmias, thepremature or abnormal beats do not produce an effective pumping actionand are experienced as “skipped” beats.

The invention may also involve assessing the heart rhythm. For example,the simplest specific diagnostic test for assessment of heart rhythm isthe electrocardiogram (abbreviated ECG or EKG). A Holter monitor is anEKG recorded over a 24-hour period, to detect arrhythmias that canhappen briefly and unpredictably throughout the day.

Other useful assessment techniques include using a cardiac eventrecorder; performing an electrophysiological (EP) study or performing anechocardiogram.

The invention may involve assessing a neuro-based biomarker. Hence, insome embodiments, the physiological parameter may be one or moreabnormal cardiac electrical signals from the subject indicative ofcardiac dysfunction. The abnormal cardiac electrical signals may bemeasured in a cardiac-related intrathoracic nerve or peripheral gangliaof the cardiac nervous system. The abnormal electric signals may be ameasurement of cardiac electric activity.

Example of assessing cardiac electrical signals include microneurographyor plasma noradrenaline concentration. Miconeurography involves usingfine electrodes to record ‘bursts’ of activity from multiple or singleafferent and efferent nerve axons [25,26]. The measurement of regionalplasma noradrenaline spillover is useful in providing information onsympathetic activity in individual organs. Following nervedepolarization, any remaining noradrenaline in the synapse, the‘spillover’, is washed out into the plasma and the plasma concentrationis therefore directly related to the rate of sympathetic neuronaldischarge [27,28,29].

Treatment of cardiac dysfunction can be assessed in various ways, buttypically involves an improvement in one or more detected physiologicalparameters (e.g. one or more of the biomarkers mentioned above), i.e.the value of the parameter in the subject is changed towards the normalvalue or normal range for that value.

For an example, in a subject having cardiac dysfunction, an improvementin a measurable physiological parameter may be a decrease in achronotropic, a dromotropic, a lusitropic and/or an inotropic response.

For example, a decrease in heart rate, conduction or heart contractility(e.g. ventricular pressure, ventricular contractility,activation-recovery interval, effective refractory period, strokevolume, ejection fraction, end diastolic fraction, stroke work, arterialelastance). The invention might not lead to a change in all of theseparameters. Suitable methods for determining the value for any givenparameter will be appreciated by the skilled person.

Therapy of cardiac dysfunction may be indicated by an improvement in theprofile of neural activity in the cardiac-related sympathetic nerve.That is, treatment of the cardiac dysfunction is indicated by the neuralactivity in the cardiac-related sympathetic nerve approaching the neuralactivity of the resting state of the subject.

The skilled person will appreciate that the baseline for any neuralactivity or physiological parameter in an individual need not be a fixedor specific value, but rather can fluctuate within a normal range or maybe an average value with associated error and confidence intervals.Suitable methods for determining baseline values are well known to theskilled person.

As used herein, a measurable physiological parameter is detected in asubject when the value for that parameter exhibited by the subject atthe time of detection is determined. A detector is any element able tomake such a determination.

In certain embodiments, the invention further comprises a step ofdetecting one or more physiological parameters of the subject, whereinthe signal is applied only when the detected physiological parametermeets or exceeds a predefined threshold value. The physiologicalparameter may be any parameter described herein. This is useful fortreatment or prevention of cardiac dysfunction.

In such embodiments wherein more than one physiological parameter isdetected, the signal may be applied when any one of the detectedparameters meets or exceeds its threshold value, alternatively only whenall of the detected parameters meet or exceed their threshold values. Incertain embodiments wherein the signal is applied by a neuromodulatory(e.g. neuroinhibitory) device/system, the device/system furthercomprises at least one detector configured to detect the one or morephysiological parameters.

A “predefined threshold value” for a physiological parameter is theminimum (or maximum) value for that parameter that must be exhibited bya subject or subject before the specified intervention is applied. Forany given parameter, the threshold value may be defined as a valueindicative of a pathological state or a disease state, or as a valueindicative of the onset of a pathological state or a disease state.Thus, depending on the predefined threshold value, the invention can beused as a prevention or a treatment. Alternatively, the threshold valuemay be defined as a value indicative of a physiological state of thesubject (that the subject is, for example, asleep, post-prandial, orexercising). Appropriate values for any given parameter would be simplydetermined by the skilled person (for example, with reference to medicalstandards of practice).

Such a threshold value for a given physiological parameter is exceededif the value exhibited by the subject is beyond the threshold value—thatis, the exhibited value is a greater departure from the normal orhealthy value for that parameter than the predefined threshold value.

The invention is useful for subjects who are at risk of developingcardiac dysfunction may be subjected to application of the signalsdescribed herein, thereby decreasing the arrhythmic burden. The cardiactesting strategies for subjects at risk of cardiac dysfunction are knownin the art, e.g. heart rate variability (HRV), baroreflex sensitivity(BRS), heart rate turbulence (HRT), heart rate deceleration capacity(HRDC) and T wave alternans (TWA). Deviation of these parameters fromthe baseline value range would be an indication of the subject being atrisk of developing cardiac dysfunction.

Other indications include when the subject has a history of cardiacproblems or a history of myocardium injury. For example, the subject hasundergone heart procedures, e.g. heart surgery. The subject may have hada myocardial infarction. The subject may have emphysema or chronicobstructive pulmonary disease. The subject may have a history ofarrhythmia or is genetically pre-disposed to arrhythmia.

For preventive use, a subject at risk of developing cardiac dysfunctionmay be subjected to signal application for x min at regular intervals,wherein x=≤3 min, ≤5 min, ≤10 min, ≤20 min, ≤30 min, ≤40 min, ≤50 min,≤60 min, ≤70 min, ≤80 min, ≤90 min, ≤120 min, or ≤240 min. The intervalmay be once every day, once every 2 days, once every 3 days etc. Theinterval may be more than once a day, e.g. twice a day, three times aday etc.

A subject suitable for the invention may be any age, but will usually beat least 40, 45, 50, 55, 60, 65, 70, 75, 80 or 85 years of age.

The invention can be used in combination with conventionalanti-arrhythmia therapies. For example, some arrhythmias, e.g. atrialfibrillation, cause blood clotting within the heart and increase risk ofembolus and stroke. Anticoagulant medications such as warfarin andheparin, and anti-platelet drugs such as aspirin can reduce the risk ofclotting. Thus, the invention can be used in combination withadministering an anticoagulant. The invention also provides ananticoagulant medicine for use in treating a subject, wherein thesubject has an implanted device/system of the invention in signalingcontact with a cardiac-related sympathetic nerve in the extracardiacintrathoracic neural circuit.

An Implantable Device/System for Implementing the Invention

An implantable device according to the invention comprises at least onetransducer, preferably an electrode, suitable for placement on or arounda cardiac-related sympathetic nerve in the extracardiac intrathoracicneural circuit. The device/system preferably also comprises a controllercoupler to the at least one transducer. The various components arepreferably part of a single physical device. As an alternative, however,the invention may use a system in which the components are physicallyseparate, and communicate wirelessly. Thus, for instance, the transducerand the controller can be part of a unitary device, or together may forma system (and, in both cases, further components may also be present toform a larger device or system e.g. a power source, a sensor, etc.).

Electrodes

Electrodes capable of controlling delivery of current to a nerve cell inorder to affect the signals passing along the nerve fiber are known inthe art [30]. Reference [35] discloses several types of electrode fornon-damaging neural tissue conduction block. The document discloses cuffelectrodes (e.g. spiral cuff, helical cuff or flat interface), and flatinterface electrodes, both of which are also suitable for use with thepresent invention. A mesh, a linear rod-shaped lead, paddle-style leador disc contact electrode (including multi-disc contact electrodes) arealso disclosed in [35] and would be suitable for use in the presentinvention. Also suitable are intrafascicular electrode, glass suctionelectrode, paddle electrode, bipolar hemi-cuff electrode, bipolar hookelectrode, percutaneous cylindrical electrode. Electrodes may bemonopolar, bipolar, tripolar, quadripolar or have five or more poles.The electrodes may fabricated from, or be partially or entirely coatedwith, a high charge capacity material such as platinum black, iridiumoxide, titanium nitride, tantalum, poly(elthylenedioxythiophene) andsuitable combinations thereof.

Reference [31] discloses separated-interface nerve electrodes, and inparticular forms of ionic coupling electrodes (for example in the formof a cuff electrode) that facilitates the application of a prolongedsingle phase current to a nerve which mitigates the kind of nerve damagedescribed elsewhere herein. This kind of electrode would be suitable foruse in the present invention.

Reference [32] discloses adjustable nerve electrodes, particularlysuited for nerve block by delivery of high frequency alternating current(HFAC). The electrodes comprises two or more contacts and logicconfigured to control, optionally selectively control, the applicationof HFAC signals through the two or more contacts, in order to controlonset response. This kind of electrode would also be suitable for use inthe present invention, particularly in combination with delivery of aHFAC or KHFAC signal.

In the examples disclosed elsewhere herein, certain types of electrodehave been used for controlling delivery of specific types of signal. Inone example described in more detail below, silver wires were placedaround a cardiac-related sympathetic nerve in the extracardiacintrathoracic neural circuit (specifically the T1-T2 paravertebralchain) and when connected to an AC signal generator they were found tobe effective for controlling delivery of a KHFAC signal (kilohertzfrequency alternating current). In another example described in moredetailed below, a 4-node carbon black coated platinum electrode wasplaced underneath or around a cardiac-related sympathetic nerve in theextracardiac intrathoracic neural circuit (specifically the T1-T2segment) and when connected to individual DC current sources was foundto be effective for controlling delivery of a DC signal, in particular acharge-balanced DC signal.

The transducer (e.g. signal electrode) is configured to be placed near,attached to or implanted within the nerve. In some embodiments, thetransducer is attached to the nerve such that it partially or fullycircumvents the nerve. Preferably, the transducer circumvents the nerveby an angle of at least 180°.

More preferably, the transducer circumvents the nerve by at an angle ofat least 270°. Put another way, the transducer preferably circumvents atleast 50% of the circumference of the nerve, and even more preferably atleast 75% of the nerve. In such embodiments, the transducer maycircumvent the nerve by an angle of one of: 180°, 210°, 240°, 270°,300°, 330°, and 360°. According to [33], increasing the contact betweenthe nerve and the transducer leads to an improved mitigation of theonset response.

The at least one transducer (e.g. at least one electrode) may attachunilaterally or bilaterally to the cardiac-related sympathetic nerve ornerves in the extracardiac intrathoracic neural circuit. The at leastone transducer may attach at a single point or at multiple points,either on a single nerve or multiple nerves. For example, the at leastone transducer may attach at a single point or at multiple points on theleft side and/or on the right side. The multiple points may be at thesame site in a cardiac-related sympathetic nerve in the extracardiacintrathoracic neural circuit. In this embodiment, the multiple pointsmay be positioned on the nerve ≤10 mm apart. Alternatively, the multiplepoints may be at different sites in the same cardiac-related sympatheticnerve in the extracardiac intrathoracic neural circuit. In this case,the sites may be y mm apart, wherein y≥1 mm, ≥2 mm, ≥3 mm, ≥4 mm, ≥5 mm,≥6 mm, ≥7 mm, ≥8 mm, ≥9 mm. Alternatively, y may be ≥10 mm, ≥20 mm or≥30 mm. In one embodiment, the sites may be ≤10 mm apart, in particularwhere the at least one electrode attaches unilaterally. For example,modulation (e.g. inhibition) may take place at multiple points in theregion between the T1-T4, optionally T1-T2 paravertebral chain and/orthe ansae subclavia. The multiple points may be in differentcardiac-related sympathetic nerves in the extracardiac intrathoracicneural circuits. For example, the inhibition may take place at both theansae subclavia, e.g. as demonstrated in Studies 1-4.

For an AC signal, the device may use a single phase signal, andtherefore provide a single signal electrode, with a ground electrodeprovided either near, attached to or implanted within the nerve (i.e. inclose proximity to the signal electrode) or remote from, even externalto the subject. Alternatively, the device may comprise a biphasicsignal, wherein two signal electrodes are provided 180° out of phase,both placed near, attached to or implanted within the nerve and in closeproximity to each other.

For a DC signal, one or more signal electrodes may be provided. Theelectrodes may be bipolar and placed (e.g.) either side of a nerve orotherwise in close proximity, in which case the DC current may flowbetween the electrodes. Alternatively, the electrodes may be monopolar,in which case the DC current may flow from the signal electrode to aremote ground electrode provided either near, attached to or implantedwithin the nerve (i.e. in close proximity to the signal electrode) orremote from, even external to the subject.

In certain embodiments, an onset response may be reduced by an adjustingthe attributes of the electrode. In particular, the electrode may beadjusted by changing geometric attributes including, but not limited to,the number of electrodes, the width of the electrodes, the orientationof the electrodes, the distance between two or more electrodes, thesurface area of the electrodes, and radial distance from the nerve axis.This is discussed in [34]. These geometric attributes may notnecessarily require a physical adjustment, the geometric attributes maybe adjusted electronically according to the method and system proposedin [34]. To this end, the invention may include one or more remoteelectrical switches for adjustment of the geometric attributes.

In certain embodiments, an onset response may be reduced by adjustingthe width of the electrode in contact with the nerve or, for a biphasicsignal, adjusting the distance between two electrodes in contact withthe nerve, where the width of the electrode and distance between twoelectrodes are defined in the direction along the nerve axis. Inparticular, increasing the width of the electrodes and/or reducing thedistance between two electrodes in contact with the nerve reduces theonset response. These electrode geometries are optimized to depolarizethe fibers in a nerve to a blocked state with minimal current, thusresulting in a reduced onset response, as discussed in [33,34].

A specific form of electrode (referred to herein as a carouselelectrode) is disclosed in [35]. The electrode has multiple electrodecontacts for contacting the nerve. In one embodiment, four contiguousmonopolar electrode contacts is provided. As described in that document,the carousel electrode is operated by continuously cycling DC pulsesacross the plurality of electrode contacts. The application of a signalusing a carousel electrode is described below.

Where it is desired to mask the onset response of an AC signal (such asa KHFAC signal), for instance by providing a DC signal (such as a DCramp), during which the AC signal commences, it is possible to provide ahybrid electrode comprising one or more nodes for providing the ACsignal and one or more nodes for providing the DC signal. In such acase, each signal may be provided to the hybrid electrode from aseparate power source.

Suitable Forms of an Electrical Signal

Signals applied according to the invention are ideally non-destructive.As used herein, a “non-destructive signal” is a signal that, whenapplied, does not irreversibly damage the underlying neural signalconduction ability of the nerve. That is, application of anon-destructive signal maintains the ability of the cardiac-relatedsympathetic nerve in the extracardiac intrathoracic neural circuit (orfibers thereof, or other nerve tissue to which the signal is applied) toconduct action potentials when application of the signal ceases, even ifthat conduction is in practice inhibited or blocked as a result ofapplication of the non-destructive signal.

The signal will usually be an electrical signal, which may be, forexample, a voltage or current. In certain such embodiments the signalapplied comprises a direct current (DC), such as a charge balanceddirect current, or an alternating current (AC) waveform, or both a DCand an AC waveform. Characteristics of inhibitory electrical waveformsfor use with the invention are described in more detail below. As usedherein, “charge-balanced” in relation to a DC current is taken to meanthat the positive or negative charge introduced into any system (e.g. anerve) as a result of a DC current being applied is balanced by theintroduction of the opposite charge in order to achieve overall (net)neutrality. However, electrical signals are just one way of implementingthe invention, and other suitable signals are described below.

A combination of charge balanced DC and AC is particularly useful formitigating the onset response that is typical of AC, particularly KHFACsignals. In these cases, a ramp DC signal, which does not induce anonset response, is applied for a short initial period to block thenerve, during or after which an AC signal is introduced (e.g. see [36]).Reference [37] discloses an onset-mitigating high frequency nerve block,wherein a ramped DC nerve block signal is applied to the nerve, followedby application of a HFAC nerve block. Such a signal may be used with thepresent invention, in particular with a hybrid electrode, as describedabove.

A particular pattern of signals suitable for mitigating onset is asignal having a DC ramp followed by a plateau and charge-balancing;followed by a first AC waveform, wherein the amplitude of the waveformincreases during the period the waveform is applied; followed by asecond AC waveform having a lower frequency and/or lower amplitude thanthe first waveform.

In certain embodiments, the signal is a kilohertz frequency alternatingcurrent (KHFAC) signal, a charge balanced direct current carousel(CBDCC) signal, or a hybrid thereof. In some embodiments, the waveformcomprises a kilohertz frequency alternating current (KHFAC) waveform, acharge balanced direct current carousel (CBDCC) waveform, or a hybridthereof.

Conduction block using electrical signals (e.g. AC and DC signals) isproduced by creating a finite region, optionally of axons, through whichaction potentials cannot pass. This region is positioned directly underthe electrode and generally extends longitudinally a few millimeters.Thus, the block effect is isolated to the immediate vicinity of theblocking electrode, with no systemic effects.

A unique characteristic of the block is the rapid reversibility of theblock when the signal is terminated. This reversibility is clearlydemonstrated in the examples where the cardiac responses return to thepre-block values.

A few hypotheses have been put forward for the mechanism by which theseelectrical signals block nerve conduction [30]. One early explanationwas the accumulation of extracellular potassium. The second more recentproposal has been that outward potassium currents overwhelm the inwardsodium currents at the nodes or axon section (in unmyelinated axons)influenced by the KHFAC and produce block. The third hypothesis hasrecently gained traction and it focuses on sodium channel inactivationas the cause of KHFAC block. Animal model studies demonstrated thatKHFAC resulted in an increased inward sodium current compared to theoutward potassium current, leading to a dynamic membrane depolarizationof a number of nodes under the electrode. This depolarization led to theinactivation of about 90% of the sodium channels in the node directlyunder the electrode. Regardless of the mechanism, application ofelectrical signals are effective in blocking neural activity.

In certain embodiments the DC waveform or AC waveform may be a square,sinusoidal, triangular, sawtooth or complex waveform. The DC waveformmay alternatively be a constant amplitude waveform. In certainembodiments the electrical signal is an AC sinusoidal waveform.

The electric signal may be applied as step change or as a ramp change incurrent or intensity.

It will be appreciated by the skilled person that the current amplitudeof an applied electrical signal necessary to achieve the intendedneuromodulation (e.g. neuroinhibitory) will depend upon the positioningof the electrode and the associated electrophysiological characteristics(e.g. impedance). It is within the ability of the skilled person todetermine the appropriate current amplitude for achieving the intendedneuromodulation (e.g. neuroinhibitory) in a given subject. For example,the skilled person is aware of methods suitable to monitor the neuralactivity profile induced by neuroinhibition.

Notwithstanding the specific examples mentioned above, both AC and DCsignals are found to be suitable for bringing about the invention. Inthe case of AC signals, it has been found that KHFAC signals are capableof creating a block in a cardiac-related sympathetic nerve in theextracardiac intrathoracic neural circuit, and an implantable deviceconfigured to generate KHFAC signals is therefore contemplated, aspecific example of which is given below in ‘Example 1’. Further detailsof the utilization of KHFAC signals in nerve conduction is found in[30].

However, as explained elsewhere herein, the use of KHFAC signals causesa problem known as transient sympatho-excitation at onset. One solutionto the onset problem may be found by using DC signals, and animplantable device configured to generate DC signals is thereforecontemplated, a specific example of which is given below. The importanceof charge balancing to avoid adverse long-term effects of DC isdescribed in [38,35] and elsewhere, and includes factors such as nervedamage from the creation of free radicals, pH shift, accumulation ofionic charges around the electrodes, and erosion of the electrodematerial. ‘Example 2’ below is configured to apply a charge-balanced DCsignal. Moreover, DC signals can have lower power requirements.

However, a constraint exists in the use of a charge-balanced DC signalin that the maximum duration of the pulse that depolarizes the cellmembrane to initiate an action potential (referred to in [38] and [35]as the cathodal phase) is limited by adverse effects mentioned above,which are a function of both pulse duration and signal amplitude. Ofcourse, the maximum duration of a single DC pulse that can be appliedwithout significant adverse effects may be insufficient to be effectivefor practising the invention; in other words, the block applied by thecathodal phase of a single charge-balanced DC pulse that does not causesignificant adverse effects does not last long enough to be of use. Asdisclosed in [35], this problem may be addressed by using a DC‘carousel’ electrode (mentioned above), whereby a plurality of electrodecontacts spaced apart along the length of the DC carousel electrodeapply a cycle of a plurality of charge balanced DC pulses, each newpulse applied by an electrode contact being temporally offset from theprevious pulse that was applied to the adjacent node. Using acharged-balanced DC carousel enables a continuous neural block along aregion of an axon without damaging the axon. ‘Example 2’ below uses a DCcarousel electrode.

The following examples describe devices configured to deliver particularkinds of AC and DC signals introduced above, and the components of thedevice used to do so. The devices also have additional components, suchas a microprocessor, power source, memory, and so on, which aredescribed in more detail below.

ELECTRODE EXAMPLE 1 Devices Configured to Deliver KHFAC

An electrode formed of silver wires is provided and connected to an ACsignal generator on the implantable device. Although silver wire is usedhere, any suitable electrode may be used, as described above. In thiscase, the electrode comprises at least one anode and at least onecathode formed of silver wires. The AC signal provided by the signalgenerator is in this case (though need not be) a biphasic square wave,wherein the signal delivered to the at least one anode is 180° out ofphase with the signal delivered to the cathode. Alternatively, the ACsignal provided by the signal generator is a biphasic sawtooth wave,such as in [39]. The AC signal provided by the signal generator mayalternatively be a sine wave.

In one example, the selected frequency of an AC signal provided by theAC signal generator and effective for producing a KHFAC block to theansae subclavia (see FIG. 2C and associated description elsewhereherein) is 5 kHz, and the selected voltage is 16 volts. The implantabledevice may be configured to deliver only this frequency and/or voltage,or may be configured to deliver signals within certain bounds of theabove-stated frequency and/or voltage. The frequency may be between 6and 26 kHz, preferably between 8 and 24 kHz, more preferably between 10and 22 kHz, still more preferably between 12 and 20 kHz, still morepreferably between 14 and 18 kHz. The voltage may be between 10 and 30volts, preferably between 12 and 28 volts, more preferably between 14and 26 volts, still more preferably between 16 and 24 volts, still morepreferably between 18 and 22 volts.

In one example, the selected frequency of the AC signal provided by theAC signal generator and effective for producing a KHFAC block to theansae subclavia (see FIG. 3 and associated description elsewhere herein)is 5 kHz, and the selected voltage is 15 volts. The implantable devicemay be configured to deliver only this frequency and/or voltage, or maybe configured to deliver signals within certain bounds of theabove-stated frequency and/or voltage. The frequency may be between 5and 25 kHz, preferably between 7 and 23 kHz, more preferably between 9and 21 kHz, still more preferably between 11 and 19 kHz, still morepreferably between 13 and 17 kHz. The voltage may be between 5 and 25volts, preferably between 7 and 23 volts, more preferably between 9 and21 volts, still more preferably between 11 and 19 volts, still morepreferably between 13 and 17 volts.

ELECTRODE EXAMPLE 2 Devices Configured to Deliver Charged Balanced DCCarousel

A 4-node charge balanced DC ‘carousel’ electrode (i.e. a carouselelectrode with four electrode contacts) is shown in FIG. 10, theelectrode being made from platinum and coated with carbon black. A DCsource, provided on the implantable device, is electrically connected toeach electrode contacts of the 4-node electrode.

The electrode nodes are spatially separated from each other but alignedalong a common axis which, when implanted, is parallel with the axis ofthe nerve fibers. In this iteration, the electrode has the followingdimensions ˜1 cm×1 cm, each node being 1.8 mm and separated from nextnode by 1 mm. Each node of the electrode has the same dimension measuredalong the axis, and preferably also has the same dimension perpendicularto the axis. The nodes are evenly spaced on the electrode. Electrodedimensions are scalable and in other iterations, dimensions can beincreased or decreased depending on size of nerve to which the electrodewith be placed.

In combination with a microprocessor (described in more detail below),each DC source is capable of generating a charge-balanced biphasic pulsewaveform. FIG. 10B shows an example of a charge-balanced biphasic pulseand the trace in FIG. 10C and at the top of FIG. 11 shows four suchpulses, shifted in time as described below. The waveform comprises acathodic phase that produces a nerve block, and an anodic ‘recharge’phase that delivers overall (net) neutrality to prevent nerve damagefrom charge build up. The pulse begins at to at which point the currentdelivered to the node on the electrodes is zero (i=0;). The pulse thenprovides a negative (cathodic) pulse component at a cathodic currenti_(c) (that produces a nerve block). The cathodic pulse component has aduration t₁. The pulse then provides a positive (anodic) pulse componentat an anodic current i_(a) (the recharge phase). The anodic pulsecomponent has a duration t₂. The pulse then returns to deliver a zerocurrent (i.e. returning to i=0) lasting for duration t₃, before reachingthe end of the pulse, also known as the interpulse interval. The pulseis charge-balanced because the total charge (a function of pulseamplitude and time) delivered by the cathodic pulse component matchesthat delivered by the anodic pulse component, leaving no residual chargeat the end of the pulse.

References [40, 41, 42] disclose other charge-balanced biphasic signalsfor producing a nerve block. In [41], the pulse width has a durationwhich is less than half of the period (i.e. 1/frequency). With a pulsewidth of this duration, the hyperpolarization phase will be shorter induration than the depolarizing phase, which leads to a reduction in theonset response. A reduction in onset response is desirable in thepresent invention. Thus, in certain embodiments, the signal has a pulsewith having a duration which is less than half of 1/frequency.

The cathodic phase of a suitable a charge-balanced biphasic pulsewaveform comprises: (i) a ‘ramp-to-plateau’ phase during which thecurrent changes from i=0 to the cathodic current i_(c); (ii) a ‘plateau’phase at the cathodic current i_(c); and (iii) a ‘ramp to recharge’phase during which the current changes from the cathodic current i_(c)to the anodic current i_(a).

The microprocessor and DC source are configured to ramp the signal fromzero to the cathodic current, and from the cathodic current to theanodic current (and optionally from the anodic current to zero). Therate of change of current (i.e. the slope of the ramp) is such that thepulses do not invoke an onset response in the nerve, as describedelsewhere herein. Reference [35] describes the importance of slowcurrent ramps, and indicates ramps and plateaus (for both cathodic/blockplateau and anodic/recharge phases) of the order of 1-3 seconds butwithout giving specific values. In their paper ‘Characterization of highcapacitance electrode for the application of direct current electricalnerve block’ [43], Vrabec, et al. suggests a various charge-balancedbiphasic DC signal waveforms. Two such waveforms have protocols whereinthe ‘ramp-to-plateau’ and ‘ramp-to-recharge’ phases are both 2 secondduration, and wherein the DC plateau is 2 seconds or 4 seconds duration,respectively (i.e. 2-2-2, and 2-4-2). This paper also discloses a CBDCwaveform protocol used to block the onset from a KHFAC signal, whereinthe ‘ramp-to-plateau’ phase has duration of 4 seconds, the DC plateauhas a duration of 7 seconds and the ‘ramp-to-recharge’ phase has aduration of 2 seconds.

In [35] the amplitude and duration of the anodic/recharge phase isindicated to be similar to the amplitude and duration of thecathodic/block phase, although no specific value are given. In Vrabec,et al., an in vitro test with a cathodic pulse (block) of 10 secondsduration followed by an anodic pulse (recharge) of 100 seconds durationwith current amplitude of 10% of the amplitude of the cathodic pulse (toprovide charge balance). A second example having a cathodic waveformprotocol of 2-4-2 provided an anodic pulse (recharge) with currentamplitude of 10% of the amplitude of the cathodic pulse. The duration ofthe anodic pulse in this example has a duration approaching 40 seconds,again to provide charge balance.

In the present invention, different CBDC waveform protocols have beenshown to be effective. In the application of a CBDC signal to the ansaesubclavia in a reactive manner (see FIG. 8A and associated descriptionelsewhere herein), a 4-10-2 protocol was utilized with a cathodiccurrent of 6 mA and an anodic current of 0.6 mA. In the application ofCBDC current to the ansae subclavia in a pre-emptive manner (see FIG. 8Band associated description elsewhere herein), a 4-7-2 protocol wasutilized with a cathodic current of 6 mA and an anodic current of 0.6mA. Cathodic current values of between 0.5 mA and 6 mA, in particular 1mA, 2 mA, 3 mA, 4 mA and 5 mA are possible, and have been tested (seeFIGS. 8C, 8D, 9A-B and associated description elsewhere herein).

In the application of a CBDC signal to the T1-T2 paravertebral chainganglion (FIG. 11B, FIG. 12 and associated description elsewhereherein), a 2-4-2 protocol was utilized with a cathodic current of 0.5-4mA.

In these examples, which utilize a 4-node CBDC carousel electrode, theanodic current is selected such that the duration of the anodic(recharge) pulse is equal to or less than 3× the duration of thecathodic pulse. In this way, the CBDC waveform at the first node hascompleted its anodic (recharge) phase and is ready to begin its nextcathodic (block) phase after the second, third and fourth nodes havecompleted their cathodic (block) phases, and so on as the carouselcycles through the nodes. In other words, for a cathodic pulse of 2-4-2protocol (e.g. 2 seconds ‘ramp-to-plateau’, 4 seconds ‘DC plateau’ and 2seconds ‘ramp-to-recharge’), the maximum duration of the anodic pulse is24 seconds (FIG. 10B). For the DC signals to be charge-balanced,therefore, the anodic current is preferably no less than one third thecathodic current (FIG. 10B). In the example of the application of aCBDCC signal to the T1-T2 paravertebral chain ganglion shown in FIG. 11,which has a cathodic current of 2.5 mA, the anodic current is preferablyno less than 0.833 mA.

In combination with the microprocessor, the DC sources are temporallyoffset and operate as a DC carousel. A single cycle of the carouselcomprises the plurality of DC sources sequentially providing theirrespective nodes with a pulse as described above, shifted in time. In acharge balanced DC carousel electrode therefore, a first cycle beginswhen the first DC source begins generating a first pulse in a cycle forapplication to the first node, after which the second DC source willgenerate a second pulse in the cycle for application to the second node,after which the third DC source will generate a third pulse in the cyclefor application to the third node, after which the fourth DC source willgenerate a fourth pulse in the cycle for application to the fourth node,after which the first cycle ends. Once the first cycle has ended, thesecond repeats as the first. The effect of the four signals applied bythe carousel electrode is to apply a substantially constant DC charge tothe nerve (see trace FIG. 10C and FIG. 11) but without a correspondingcharge imbalance.

Theoretically, a minimum of 2 nodes is required for CBDCC, although morecould be provided, as long as the periodicity of the signals applied bythe nodes is compensated accordingly. However, to implement the presentinvention, a minimum of 4 nodes and preferably exactly 4 nodes, ispreferred.

Because each of the nodes on a DC carousel is driven by its own DCsource, and the efficacy of the block is current dependent, the currentdelivered to each node can be tuned as necessary to adjust the currentdelivered to the nerve, and thus the block applied to each part of thenerve contacting the nodes.

Thus, a DC carousel electrode may comprise multiple nodes for DC currentapplication, wherein each node is sequentially controlled in serial orrandom sequence. The current applied to a node of the DC carouselelectrode may be applied as charged balanced waveform.

Other Suitable Forms of Transducer and Signal

The signal may comprise an ultrasonic signal. In certain suchembodiments, the ultrasonic signal has a frequency of 0.5-2.0 MHz,optionally 0.5-1.5 MHz, optionally 1.1 MHz. In certain embodiments, theultrasonic signal has a density of 10-100 W/cm², for example 13.6 W/cm²or 93 W/cm².

Another mechanical form of neuromodulation (e.g. neuroinhibition) usesultrasound which may conveniently be implemented using external insteadof implanted ultrasound transducers.

The signal may comprise an electromagnetic signal, such as an opticalsignal. Optical signals can conveniently be applied using a laser and/ora light emitting diode configured to apply the optical signal. Incertain such embodiments, the optical signal (for example the lasersignal) has an energy density from 500 mW/cm² to 900 W/cm². In certainalternative embodiments, the signal is a magnetic signal. In certainsuch embodiments, the magnetic signal is a biphasic signal with afrequency of 5-15 Hz, optionally 10 Hz. In certain such embodiments, thesignal has a pulse duration of 1-1000 μs, for example 500 μs.

The signal may use thermal energy, and the temperature of a nerve can bemodified to inhibit propagation of neurosignaling. For example, Patberget al. [44] discuss how cooling a nerve blocks signal conduction withoutan onset response, the block being both reversible and fast acting, withonsets of up to tens of seconds. Heating the nerve can also be used toblock conduction, and is generally easier to implement in a smallimplantable or localized transducer or device, for example usinginfrared radiation from laser diode or a thermal heat source such as anelectrically resistive element, which can be used to provide a fast,reversible, and spatially very localized heating effect (e.g. [45]).Either heating, or cooling, or both could be conveniently provided invivo using a Peltier element.

Where the signal applied to a nerve is a thermal signal, the signal canreduce the temperature of the nerve. In certain such embodiments thenerve is cooled to 14° C. or lower to partially inhibit neural activity,or to 6° C. or lower, for example 2° C., to fully inhibit neuralactivity. In such embodiments, it is preferably not to cause damage tothe nerve. In certain alternative embodiments, the signal increases thetemperature of the nerve. In certain embodiments, neural activity isinhibited by increasing the nerve's temperature by at least 5° C., forexample by 5° C., 6° C., 7° C., 8° C., or more. In certain embodiments,signals can be used to heat and cool a nerve simultaneously at differentlocations on the nerve, or sequentially at the same or differentlocation on the nerve.

In [34], inhibiting propagation of neurosignaling by cooling the nervemay also reduce the onset response. Accordingly, cooling may be used inthe present invention combination with the DC and HFAC embodimentsdescribed above. To this end, the device/system of the present inventionmay comprise at least one transducer comprising a cooling element. Thecooling element may take the form of a Peltier element provided in vivo.

The signal may use microwave signal to heat magnetic nanoparticles thatabsorb RF radiation, thereby heating surrounding tissue. A techniqueinvolving combining magnetic nanoparticles with proteins known to bindto specific protein targets on neural cell membranes.

Microprocessor

The implantable device may comprise a microprocessor. The microprocessormay be responsible for triggering the beginning and/or end of the signaldelivered to the cardiac-related sympathetic nerve in the extracardiacintrathoracic neural circuit by the at least one transducer. Optionally,the microprocessor may also be responsible for generating and/orcontrolling the parameters of the signal.

The microprocessor may be in electrical communication with the signalgenerator, and the microprocessor may trigger the beginning and/or endof the signal delivered to the cardiac-related sympathetic nerve bycommunicating with the signal generator. An exemplary pulse generatorwith a processor configuration suitable for nerve stimulationapplications is disclosed in ref.14.

The microprocessor may be configured to operate the device/system in anopen-loop fashion, wherein a pre-defined signal (e.g. as describedabove) for treatment or prevention is delivered to a cardiac-relatedsympathetic nerve in the extracardiac intrathoracic neural circuit at agiven periodicity (or continuously) and for a given duration (orindefinitely) without any external trigger, control or feedbackmechanism. Alternatively, the microprocessor may be configured tooperate the device/system in a closed-loop fashion, wherein a signal isapplied based on an external trigger, control or feedback mechanism.

The microprocessor of the device may be constructed so as to generate,in use, a preconfigured and/or user-selectable signal that isindependent of any input. Preferably, however, the microprocessor isresponsive to an external signal, more preferably information pertainingto a physiological response in the subject.

As is well known, and described elsewhere herein, implantablecardioverter defibrillator (ICD) devices are known to be configured todetect physiological signals indicative of cardiac dysfunctions andabnormal heart rhythms, and upon detection perform one or more therapiesincluding cardioversion, defibrillation and pacing of the heart.Indicative physiological signals include a decrease in ventricularpressure, a decrease in ventricular contractility, a decrease in heartrate, a decrease in activation-recovery interval and prolonged effectiverefractory period. An exemplary ICD device which monitors cardiacelectrical activity, recognizes ventricular fibrillation and ventriculartachyarrhythmias with a sinusoidal wave form, and then deliverscorrective defibrillatory discharges is disclosed in [46].

The implantable device of the present invention may comprise circuitrysimilar to that found in an ICD to detect physiological signalsindicative of cardiac dysfunctions and abnormal heart rhythms, and usethese signals to trigger the microprocessor to communicate to the signalgenerator to deliver a signal of the kinds described above (for examplein Examples 1 and 2 above) to the cardiac-related sympathetic nerve inthe extracardiac intrathoracic neural circuit using the at least onetransducer.

The circuitry may comprise one or more sensors placed on parts of thebody to detect physiological signals. These may include one or moreelectrodes placed on or around one or more ventricles of the heart todetect electrical activity; pressure and/or spatial sensors placedwithin a ventricle and configured to measure ventricular pressure,conduction and/or contractility.

Upon receipt of signals received from the one or more sensors, theprocessor may calculate the current heart rhythms, including heart rate,activation-recovery interval and effective refractory period, inaccordance with techniques known in the art.

The device may comprise memory for storing physiological data pertainingto a normal heart rhythm. The data may be specific to the patient intowhich the device is implanted, and gleaned from various tests known inthe art. Upon receipt of signals received from the one or more sensors,or else periodically or upon demand, the processor may compare thesignals received from the one or more sensors with the physiologicaldata stored in the memory and determine whether the received signals areindicative of a cardiac dysfunction or abnormal heart rhythm. The devicemay be configured such that if and when a cardiac dysfunction orabnormal heart rhythm is indicated, the processor communicates to thesignal generator, and the signal generator triggers delivery of a signalto the cardiac-related sympathetic nerve in the extracardiacintrathoracic neural circuit by the at least one transducer.

A device according to the invention configured to operate in aclosed-loop fashion may be configured to apply one or both of apre-emptive block or a reactive block (by contrast, a device configuredto operate in an open-loop fashion is configured to apply a pre-emptiveblock only).

In a device configured to operate in a closed-loop fashion, apre-emptive block may be applied when the signals received by the one ormore sensors are indicative of a cardiac dysfunction or abnormal heartrhythm that has yet to initiate. Once such signals are detected andcompared with stored data (as described above), the processor may beconfigured to communicate to the signal generator to deliver a signal tothe cardiac-related sympathetic nerve in the extracardiac intrathoracicneural circuit by the at least one transducer in advance of theinitiation of the cardiac dysfunction or abnormal heart rhythm.

In a device configured to operate in an open-loop fashion, a reactiveblock may be applied when the signals received by the one or moresensors are indicative of a cardiac dysfunction or abnormal heart rhythmthat is taking place. Once such signals are detected and compared withstored data (as described above), the processor may be configured tocommunicate to the signal generator to deliver a signal to thecardiac-related sympathetic nerve in the extracardiac intrathoracicneural circuit by the at least one transducer during the cardiacdysfunction or abnormal heart rhythm (see FIG. 8A and associateddescription elsewhere herein).

As an alternative to the sensing circuitry similar of an ICD whichdetects cardiac electrical activity indicative of cardiac dysfunctionsand abnormal heart rhythms, a device according to the invention thatoperates in a closed-loop fashion could include circuitry that senses aneural activity in a cardiac-related sympathetic nerve or ganglia in theextracardiac intrathoracic neural circuit. The sensing circuitry maycomprise one or more transducers, preferably electrodes, of any of thekinds described above that are suitable for sensing neural activity, asknown in the art.

In response to neural activity, the processor may determine whether thereceived signals are indicative of a cardiac dysfunction or abnormalheart rhythm and, if and when a cardiac dysfunction or abnormal heartrhythm is indicated, the processor may communicates to the signalgenerator, and the signal generator trigger delivery of a signal to thecardiac-related sympathetic nerve in the extracardiac intrathoracicneural circuit by the at least one transducer.

As an alternative, or in addition, to the device's ability to respond tosensed physiological signals, the processor may communicate to thesignal generator, and the signal generator may be triggered, uponreceipt of a signal generated by a physician or by the subject in whichthe device is implanted. To that end, the implantable device may be partof a system comprising subsystems external to the subject, andincluding, for instance, a controller. An example of such a system isdescribed below.

The controller may be configured to communicate to the signal generatorto apply a signal to the cardiac-related sympathetic nerve in theextracardiac intrathoracic neural circuit intermittently orcontinuously. Suitable signals for use with the invention are discussedabove. Intermittent inhibition involves applying the modulation (e.g.inhibition) in an (on-off). pattern, where n>1. For instance, modulation(e.g. inhibition) can be applied continuously for at least 5 days,optionally at least 7 days, before ceasing for a period (e.g. 1 day, 2days, 3 days, 1 week, 2 weeks, 1 month), before being again appliedcontinuously for at least 5 days, etc. Thus inhibition is applied for afirst time period, then stopped for a second time period, then reappliedfor a third time period, then stopped for a fourth time period, etc. Insuch an embodiment, the first, second, third and fourth periods runsequentially and consecutively. The duration of the first, second, thirdand fourth time periods is independently selected. That is, the durationof each time period may be the same or different to any of the othertime periods.

In certain such embodiments, the duration of each of the first, second,third and fourth time periods may be any time from 1 second (s) to 10days (d), 2 s to 7 d, 3 s to 4 d, 5 s to 24 hours (24 h), 30 s to 12 h,1 min to 12 h, 5 min to 8 h, 5 min to 6 h, 10 min to 6 h, 10 min to 4 h,30 min to 4 h, 1 h to 4 h. In certain embodiments, the duration of eachof the first, second, third and fourth time periods is 5 s, 10 s, 30 s,60 s, 2 min, 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 90min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h, 2 d, 3 d,4 d, 5 d, 6 d, 7 d. Intermittent inhibition may also be referred to asperiodic inhibition, where the periodic pattern is the on-off patterndescribed above. Intermittent inhibition may be thought of as temporallyselective treatment of cardiac dysfunction according to the on-offpattern.

In certain embodiments, modulation (e.g. inhibition) is applied for aspecific amount of time per day. In certain such embodiments, the signalis applied for 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 90 min, 2h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h per day. In certainsuch embodiments, modulation (e.g. inhibition) is applied continuouslyfor the specified amount of time. In certain alternative suchembodiments, modulation (e.g. inhibition) may be applied discontinuouslyacross the day, provided the total time of application amounts to thespecified time.

Continuous modulation (e.g. inhibition) may continue indefinitely, e.g.permanently. Alternatively, the continuous application may be for aminimum period, for example the signal may be continuously applied forat least 5 days, or at least 7 days.

Where modulation (e.g. inhibition) is controlled by a device/system ofthe invention, and where a signal is continuously applied to the nerve,although the signal might be a series of pulses, the gaps between thosepulses do not mean the signal is not continuously applied.

In certain embodiments, modulation (e.g. inhibition) is applied onlywhen the subject is in a specific state e.g. only when the subject isawake, only when the subject is asleep, prior to and/or after theingestion of food, prior to and/or after the subject undertakesexercise, etc.

These various embodiments for timing of modulation (e.g. inhibition) canall be achieved using the controller, preferably external controller, ina device/system of the invention. In one embodiment, the controller isan external controller.

Other Components of the Implantable Device

The implantable device may be powered by a power source, which maycomprise a current source and/or a voltage source for providing thepower for the signal delivered to the cardiac-related sympathetic nervein the extracardiac intrathoracic neural circuit by the at least onetransducer. The power source may also provide power for the othercomponents of the device, such as the microprocessor, memory andcommunication subsystem (described below). The power source may comprisea battery and may be rechargeable. It will be appreciated that theavailability of power is limited in implantable devices, and theinvention has been devised with this constraint in mind. Thedevice/system may be powered by inductive powering or a rechargeablepower source.

The implantable device may comprise a communication subsystem, forinstance comprising a transceiver coupled to the processor. Thetransceiver may use any suitable signaling process such as RF, wireless,infrared and so on, for transmitting signals outside of the body, forinstance to a system of which the implantable device is one part.

System Including Implantable Device

The implantable device of the invention may be part of a system thatincludes a number of subsystems. For instance, the system may comprisesubsystems located outside of the body, including a subsystem forwirelessly recharging the battery used to power the implantable device,and a controller with a communications subsystem that is configured tocommunicate with the communications subsystem of the implantable device.

The controller may comprise an actuator which, upon being pressed by aphysician or the subject for instance, will deliver a signal, via therespective communications subsystems, to trigger the processor of theimplantable device to deliver a signal to the cardiac-relatedsympathetic nerve in the extracardiac intrathoracic neural circuit bythe at least one transducer. Suitable signals for use with the inventionare discussed above.

The controller may also be configured to make adjustments to theoperation of the implantable device. For instance, it may transmit, viathe respective communications subsystems, physiological data pertainingto a normal heart rhythm. The data may be specific to the patient intowhich the device is implanted. The controller may also be configured tomake adjustments to the operation of the power source, signal generationand processing elements and/or electrodes in order to tune the signalcurrent delivered to the cardiac-related sympathetic nerve in theextracardiac intrathoracic neural circuit by each node of the electrode.

A device/system of the invention is preferably made from, or coatedwith, a biostable and biocompatible material. This means that thedevice/system is both protected from damage due to exposure to thebody's tissues and also minimizes the risk that the device/systemelicits an unfavourable reaction by the host (which could ultimatelylead to rejection). The material used to make or coat the device/systemshould ideally resist the formation of biofilms. Suitable materialsinclude, but are not limited to, poly(p-xylylene) polymers (known asParylenes) and polytetrafluoroethylene.

A device/system of the invention will generally weigh less than 50 g.

General

The term “comprising” encompasses “including” as well as “consisting”e.g. a composition “comprising” X may consist exclusively of X or mayinclude something additional e.g. X+Y.

The word “substantially” does not exclude “completely” e.g. acomposition which is “substantially free” from Y may be completely freefrom Y. Where necessary, the word “substantially” may be omitted fromthe definition of the invention.

The term “about” in relation to a numerical value x is optional andmeans, for example, x±10%.

Unless otherwise indicated each embodiment as described herein may becombined with another embodiment as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram depicting the gross anatomic arrangementof the upper thoracic paravertebral chain (T1-T4) and associatedmediastinal neural structures, including stellate and middle cervical(MCG) ganglia.

FIGS. 2-7 demonstrate the application of the invention using kilohertzfrequency alternating current (KHFAC). FIGS. 8-15 demonstrate theapplication of the invention using direct current (DC).

FIG. 2A is a schematic diagram showing the experimental set up for theresults shown in the FIGS. 2-5. KHFAC was delivered to the ansaesubclavia in dogs (inset for FIG. 2A). Electrical stimulation (RSS) wasapplied to the stellate ganglion upstream of the ansae subclavia toactivate sympathetic efferent projections to the heart.

FIG. 2B shows the evoked cardiac responses to the stimulation of theleft stellate ganglion (4 Hz; depicted by “ON” and “OFF”). Panelsshowing the following parameters over time (from bottom): heart rate(beats/min), left ventricular pressure (LVP; mmHg) and left ventricularcontractility (as reflected in the changes in LV dP/dt; mmHg/s).

FIG. 2C shows the evoked cardiac responses to KHFAC and RSS delivery.Panels show the following parameters over time (from bottom): leftventricular pressure (LVP; mmHg); heart rate (beats/min); leftventricular contractility (LV dP/dt; mmHg/s); stellate cardiac ganglionstimulation (RSS), KHFAC delivery at 5 kHz, 16 V, biphasic square wave).Box: onset response to KHFAC.

FIG. 3A shows the percentage change in the heart rate over the initial120 seconds after onset of KHFAC delivery at different frequencies: 5kHz (Δ), 10 kHz (▾), 15 kHz (∘) and 20 kHz (●).

FIG. 3B shows the percentage change in the left ventricularcontractility (LV +dP/dt) over the initial 120 seconds after onset ofKHFAC delivery at different frequencies: 5 kHz (Δ), 10 kHz (▾), 15 kHz(∘) and 20 kHz (∘).

FIG. 3C shows the percentage change in heart rate in response to RSSbefore (black bars) and during KHFAC delivery. KHFAC delivered atfrequencies of 5 kHz, 10 kHz, 15 kHz and 20 kHz.

FIG. 3D shows the percentage change in LV +dp/dt in response to RSSbefore (black bars) and during KHFAC delivery. KHFAC delivered atfrequencies of 5 kHz, 10 kHz, 15 kHz and 20 kHz.

FIG. 4 show effects of KHFAC delivered to the ansae on the RSS evokedchanges in LV +dp/dt (FIG. 4A) and heart rate (FIG. 4B). Bars from leftto right: before KHFAC delivery (RSS at 0.54 mA); RSS delivered duringKHFAC (10 kHz, 15V); RSS delivered 10′, 23′ and 29′ after KHFACtermination. Last three bars indicate cardiac responses to increasingRSS stimulus intensity to 0.6 mA, 0.65 mA and 0.7 mA.

FIG. 5A is a schematic diagram showing the experimental set up for theresults shown in FIGS. 5-7 for evaluation of KHFAC. The schematicdiagram depicts the gross anatomic arrangement of the porcineright-sided upper thoracic paravertebral chain (T1-T4) and the lowercervical paravertebral chain. SG=stellate ganglion. MCG=middle cervicalganglion. CPN=cardiopulmonary nerves. “X” depicts KHFAC delivery sitesat the ansae sublavia and the “open circle” depicts KHFAC delivery sitesat the T1-T2 paravertebral chain. Lightning bolts indicate RSSstimulation sites at the T3 paravertebral chain and at the C8-T1paravertebral chain.

FIG. 5B shows the evoked cardiac responses to KHFAC delivery to theansae subclavia and RSS delivery at the T3 ganglion prior to and duringKHFAC. Panels show the following parameters over time: (from bottom)electrocardiac diagram (ECG); heart rate (beats/min); left ventricularpressure (LVP; mmHg); left ventricular contractility (LV dP/dt; mmHg/s);stellate stimulation (RSS); KHFAC delivery (15 kHz, 15 Volts, biphasicsquare wave) to the ansae subclavia. Boxed: onset response.

FIGS. 6A-6D show the percentage change in heart rate (FIGS. 6A and 6C)and the percentage change in left ventricular contractility (LV +dp/dt;FIGS. 6B and 6D), respectively, in response to the left-sided (LT3;FIGS. 6C and 6D) and right-sided stellate T3 (RT3; FIGS. 6A and 6B)paravertebral chain ganglion stimulation before, during and after KHFACdelivery to the T1-T2 paravertebral chain ganglion. * p<0.05 fromcontrol.

FIG. 7 shows the percentage change in heart rate (Δ), percentage changein contractility (LV +dp/dt; B) and percentage change inactivation-recovery interval (ARI; C) at KHFAC onset when delivered atvarying frequencies (5 kHz to 20 kHz) and voltages (5 to 20 V).

FIGS. 8-12 demonstrate the application of the invention using directcurrent (DC).

FIGS. 8A and B shows the evoked cardiac responses when direct current(DC; A: 4-10-2, 6 mA/0.6 mA; B: 4-7-2, 6 mA/0.6 mA) was delivered to theansae subclavia in a reactive (A) and a pre-emptive (B) manner. Panelsfrom the bottom show the following parameters over time: heart rate(beats/min); left ventricular pressure (LVP; mmHg); left ventricularcontractility (LV dp/dt; mmHg/s); right stellate ganglion stimulation(Grass); DC delivery.

FIGS. 8C and 8D show the percentage of block of heart rate andcontractility (dP/dt+), respectively, when DC was delivered at 3.0 mAand 6.0 mA. Black bars=pre-emptive. gray bars=reactive.

FIG. 9 shows the percentage of block of the RSS induced changes in heartrate (FIG. 9A) and LV contractility (FIG. 9B) during DC delivery to theansae subclavia at amplitudes ranging from 0 mA to 6 mA.

FIG. 10 is a schematic diagram showing the experimental set-up for FIGS.11-12, 14 and 15. The schematic diagram depicts the gross anatomicarrangement of the porcine right-sided upper thoracic paravertebralchain (T2-T4) and associated mediastinal neural structures, includingstellate (SG) and middle cervical (MCG) ganglia. Four DC electrodes arecoupled to the region between T1-T2 paravertebral chain ganglion, andthey are arranged to deliver signals one after another in cycles (DCcarousel; DCC). Arrows indicate stimulation sites at the T2paravertebral chain and at the stellate ganglion (insert for FIG. 10).

FIG. 10B shows an exemplary charged balanced biphasic DC pulse. In thisinteration, there is a 2 second ramp down to a 4 second plateau, with atwo second ramp up to a current in the opposite direction that is ˜⅓ ofthe plateau current and maintained for ˜16 second. The critical factoris that charge delivery during the recharge phase balances thatdelivered during ramp and plateau phase.

FIG. 10C shows an example of one cycle of charge balanced DC currentdelivery, in this case from four channel (node) electrode. In thisinteration, by the time node 4 has finished its plateau phase, the firstnode is available for re-stimulation, thus allowing for longer-durationcharge balanced DC carousel (CBDCC) bioelectric modulation.

FIG. 11 shows the evoked cardiac response to the T2 paravertebral chainganglion stimulation before, during and after DC delivery to the T1-T2paravertebral chain ganglion. Panels show the following parameters overtime: (from bottom) left ventricular pressure (LVP; mmHg); leftventricular contractility (LV dp/dt; mmHg/s); heart rate (beats/min); DCdelivery (2.5 mA, 2-4-2 1 cycle); RSS stimulation of the right T2ganglion.

FIG. 12A shows the percentage change in heart rate, left ventricularcontractility (LV dP/dt+) and activation-recovery interval (ARI)relative to the baseline in response to T2 stimulation (black bars) orin response to one cycle of charge balanced DC current (grey bars).

FIGS. 12B-D shows the percentages change T2 evoked changes in heart rate(B), left ventricular contractility (LV dP/dt+; C) and ventricularactivation-recovery interval (ARI; D) at different amplitudes of DCcurrent, all delivered as CBDCC. Negative values indicate suppression ofT2 evoked response. Data for various animals are shown: DC6 (●), DC8(∘), DC10 (▾), DC11 (Δ), DC12 (▪), DC13 (□), DC14 (♦).

FIG. 13 shows the MRI image of a porcine heart at 6 weeks followinginduced MI.

FIG. 14 shows the effects of T2 stimulation on heart rate (Δ), LV +dp/dt(B) and activation recovery interval of the ventricle (ARI, C) prior to(T2 Pre), during CBDCC, and following CBDCC (T2 Post). * p.0.02 vs T2.

FIG. 15A shows ventricular arrhythmia inducibility of the chronic MImodel pigs. Left bar: baseline; right bar: during CBDCC delivery. *P<0.05.

FIG. 15B shows the effects of CBDCC on S2 effective refractory period inthe chronic MI model pigs. P<0.05 vs baseline.

MODES FOR CARRYING OUT THE INVENTION

Study I—KHFAC

This study investigated the evoked cardiac responses to the delivery ofKHFAC at a nodal intervention point in dogs. The communication betweenstellate and middle cervical ganglia, namely the ansae subclavia, wastargeted for neural block, and the experimental set up is shown in FIG.2A. Stellate ganglion simulation (RSS) was delivered by Grass S88Stimulator at 4 Hz. KHFAC was delivery to the ansae subclavia by avoltage controlled block (Stanford Research Systems DS 345 waveformgenerator). Cardiac readouts, indicative of functional sympatheticinputs to the heart, included heart rate (beats/min), ventricularcontractility (+dP/dt), and ventricular pressure (LVP) were recorded.

The results are shown in FIGS. 2-5 b. KHFAC delivery to the ansaesubclavia successfully evoked changes in regional cardiac function.

The stimulation of the stellate ganglion (RSS) led to an increase incardiac contractility and heart rate (FIG. 2B). The increase incontractility and heart rate was reduced by KHFAC delivery (5 kHz, 16 V,biphasic square wave) to the ansae subclavia (FIG. 2C). During KHFACdelivery, the cardiac responses to sympathetic efferent activation wereblunted.

The sympathetic neurons also demonstrated a delayed recovery (FIGS. 2Cand 4) showing that a small duration of KHFAC delivery could induceprolonged block of up to 30 minutes.

A clear dose response was also identified in FIGS. 3 and 4 with blockinglevels related to frequency and intensity among other factors.

KHFAC evoked a transient sympatho-excitation at onset that wasvoltage-dependent and inversely related to frequency (see FIG. 2C, 3Aand 3B), but was nonetheless efficacious in reducing sympatheticactivation after the initial onset phase (FIGS. 3C, 3D and 4).

Thus, this study demonstrates that sympathetic signals to the heartcould be blocked by applying electrical signals, e.g. KHFAC, to theansae subclavia.

Study 2—KHFAC

This study investigated the reversibility of cardiac responses to KHFACdelivery to either the ansae subclavia or the T1-T2 paravertebral chainganglion in pigs.

The experimental set up is outlined in FIG. 5A. KHFAC (15 kHz, 15 Volts,biphasic square wave) was delivered at either the T1-T2 paravertebralchain ganglion or ansae subclavia. Electrical simulation to activatesympathetic efferents was delivered at either the T3 paravertebral chainor the C8-T1 paravertebral chain (location of stellate ganglion).

KHFAC Delivery to Ansae Subclavia

The effects of KHFAC delivery to the ansae subclavia are shown in FIG.5B. Referring to FIG. 5B, stellate stimulation led to an increase incardiac function (increase in heart rate, increase in left ventricularpressure and increase in left ventricular contractility). This increasewas reduced by KHFAC delivery to the ansae subclavia. During KHFACdelivery, further stellate stimulation resulted in minimum cardiacresponses.

KHFAC Delivery to T1-T2 Paravertebral Chain Ganglion

The effects of KHFAC delivery to the T1-T2 paravertebral chain ganglionare shown in FIG. 6. It can be seen that chronotropic (FIGS. 6A and 6C)and inotropic (FIGS. 6B and 6D) functions in response to T3 stimulationwas significantly reduced during KHFAC delivery, and the reductions inevoked responses reversed after KHFAC delivery.

Onset Response

The onset response following KHFAC was further investigated. Inparticular, the chronotropic, inotropic and dromotropic responses weremeasured with KHFAC delivery at varying frequencies and voltages, andthe results are shown in FIG. 7.

It was considered that KHFAC onset response reflects transientactivation of underlying nerve tracts prior to block induction. It seemsthat, for the onset response, lower frequency ranges with higherintensities generate bigger onset responses. The onset response may beminimized by modifying parameters and studying the effect, for exampleby (1) lowering the frequency, lowering intensity and changing thewaveform, or (2) ramp titration starting from high frequency-lowintensity to target levels. For example, Ackermann et al. [47]demonstrated that onset response may be completely neutralized by usinga brief DC nerve block prior to application of the KHFAC signal. The useof KHFAC in combination with a DC nerve block is also contemplated forthe present invention.

Thus, this study demonstrates the reversibility of the block of thesympathetic signals to the heart by applying electrical signals, e.g.KHFAC, to either the ansae subclavia or the T1-T2 paravertebral chainganglion.

Study 3—DC

This study investigates the evoked cardiac responses to DC delivery at anodal intervention point. This study is set up in a similar way as theprevious studies, except DC was delivered to the ansae subclavia. Thisstudy was done in both canine and porcine models.

The results are shown in FIG. 8. These experiments were done in theanesthetized canine model. It can be seen that DC block was effective ina reactive and pre-emptive manner. In particular, FIG. 8A shows that DCblock was effective when used in a reactive manner. When DC wasdelivered during right stellate stimulation (RSS), the increase in thechronotropic and inotropic functions in response to RSS stimulation wasreduced during the period of DC delivery.

FIG. 8B shows that DC block was effective when used in a pre-emptivemanner. When DC was delivered at the onset of RSS stimulation, theincrease in the chronotropic and inotropic functions in response to RSSstimulation was not achieved until after DC delivery was removed.

Interestingly, the percentages block of chronotropic (FIG. 8C) andinotropic (FIG. 8D) responses were highly effective for DC pre-emptiveuse, with 80% block at 3 mA, and increasing to nearly 100% at 6 mA, forboth inotropic and chronotropic responses.

Thus, this study has established for the first time that neural block ofcardiac sympathetic regulation at a nodal intervention was effective forreactive, and particularly effective for pre-emptive, treatments ofventricular arrhythmias.

Study 4—DC

This study investigated the cardiac responses to DC delivery withincreasing voltages. These experiments were done in the anesthetizedcanine model. The results are shown in FIG. 9.

FIG. 9 shows that increasing the DC voltage/current amplitude increasesthe percentage block of chronotropic (FIG. 9A) and inotropic (FIG. 9B)responses.

Therefore, increasing current output was able to produce substantiallygreater DC block. As a corollary, the degree of block can be graded byselecting the current intensity.

Study 5—DCC

This study investigated the cardiac responses to delivery of DC carousel(DCC). The experimental set up is shown in FIG. 10. DC was delivered tothe T 1-T2 paravertebral chain ganglion and ganglion stimulation wasdelivered at the T2 paravertebral chain and stellate ganglion (SG).

In Yorkshire pigs a median sternotomy was performed, the right thoracicparavertebral chain isolated and a 56-electrode sock placed over theventricular epicardium. For charged balanced DC (CBDC), a 4-node CBDCCcarbon black coated platinum electrode was placed under the T1-T2segment (FIG. 10) and connected to individual DC current sources. T2electrical stimulation with and without CBDCC, delivered at varyingcurrent intensities, was used to determine local block efficacy. Cardiacreadouts, indicative of functional sympathetic inputs to the heart,included activation recovery interval (ARI), heart rate and leftventricular (LV) +dP/dt were recorded.

The inventors noted that, with this design, a minimum of four nodes arerequired for maintained DCC block because of technical issues withcharge-balance. FIGS. 10B and 10C show an illustrative waveform for asingle node (FIG. 10B) or for the stimulation protocol for a 4 nodeCBDCC stimulation. FIG. 10C reflects a single cycle through the 4 nodeswhich can then be linked serially to maintain DC block.

The results are shown in FIGS. 11-12. CBDCC was effective in modulatingsympathetic efferent projections to the heart.

FIG. 11 shows the cardiac responses to DCC delivery to the T1-T2ganglion. Referring to FIG. 11, stellate stimulation led to an increasein cardiac function (increase in heart rate, left ventricular pressureand left ventricular contractility). This increase was reduced by DCCdelivery to the T1-T2 ganglion. Interestingly, once DCC delivery wasremoved, baseline cardiac function resumed.

It was also found that increasing the DCC voltage/current amplitudeincreases the block of chronotropic (FIG. 12B), inotropic (FIG. 12C) anddromotropic (FIG. 12D) responses. Note also that CBDCC had minimalimpact on basal cardiac function (FIG. 12A, grey bars).

Conclusion

This study confirmed that nodal intervention by DCC block at the upperthoracic paravertebral chain, (namely T1-T2) is highly effective inreducing the sympathetic regulation of cardiac function. Interestingly,the efficacy of a DCC block is current dependent, and because of this,each node for the DC block can be tuned to a desired degree of block byadjusting the current.

T1 stimulation proximal (upstream) to the block resulted in maintainedsympathetic response.

Notably, the effects of DCC (short-term) on the nerve are reversible, soit does not alter basal cardiac function.

Study 6—DCC in Porcine Chronic MI model

This study investigated the efficacy of charge balanced direct current(CBDC), applied to the T1-T2 region of the paravertebral chain in acarousel arrangement (CBDCC), to impact the ventricular arrhythmiapotential post-myocardial infarction (MI).

This study used a porcine chronic myocardial infarction (MI) model(n=7). In the porcine models, MI was induced beyond the first diagonalin the left anterior descending coronary artery by microsphereinjection. FIG. 13 shows a representative MRI illustrating themyocardial infarct zone so created. Terminal procedures were performed(8-16 weeks) thereafter. At termination, following a mid-sternalthoracotomy, a 56-epicardial-electrode sock was placed over bothventricles and a quadripolar carousel electrode positioned underlyingthe right T1-T2 paravertebral chain. The efficacy of CBDC carousel(CBDCC) block was assessed by stimulating the right T3 paravertebralganglion with and without CBDCC. Ventricular tachycardia (VT)inducibility to a S1-S2 pacing protocol was then assessed at baseline(BL) and repeated under >50% CBDCC blockade of functional sympatheticefferent projections to the heart.

The results are shown in the table below and in FIGS. 14-15.

FIG. 14 illustrates the efficacy of CBDCC to reduce sympathetic inputsto the heart as reflected in the blunted responses to T2 stimulation forheart rate (FIG. 14A), LV +dp/dt (FIG. 14B) and ventricular activationrecovery interval (ARI, FIG. 14C). As with normal animals, the effectsof CBDCC were readily reversible as is evident in the T2 responsesevoked post DC block (T2 post, all three panels, FIG. 14 A-C).

As shown in FIG. 15A, VT was induced at baseline in all animals. Onlyone animal was re-inducible for VT with simultaneous CBDCC application(p<0.002 from baseline).

As shown FIG. 15B, S2 effective refractory period (ERP) was prolongedwith DCC (323±26 ms) compared to baseline (271±32 ms) (p<0.05).

Table 1 shows that application of the DCC block resulted in reducedcontractility and left ventricle end systolic pressure in some pigs butoverall did not significantly alter basal cardiac function. Thisincludes ARI which was not altered compared to baseline.

TABLE 1 Cardiac function in in porcine chronic MI model with and withoutDCC block. Baseline DC HR dP/dt+ LVESP HR dP/dt+ LVESP MI 01 56 1744 14267 1764 137 MI 02 75 1346 134 72 713 62 MI 04 65 1419 104 86 1182 89 MI05 64 1350 119 61 819 66 MI 06 64 1359 106 75 1383 105 MI 07 88 890 8091 490 86

In summary, axonal modulation of the T1-T2 paravertebral chain withCBDCC significantly reduced ventricular arrhythmias in a chronic MImodel by 83%. CBDCC altered S2 ERP, without altering baseline ARI,resulting in improved electrical stability.

Conclusion

These studies demonstrated that intervention (e.g. blocking) of the(e.g.) efferent sympathetic nervous system (particularly at the T1-T2paravertebral ganglia and ansae subclavia) by electrical signals isuseful for treating or preventing cardiac dysfunction such asventricular arrhythmias post-myocardial infarction. The electricalsignals reversibly block the efferent system to heart, therebyoverriding sympathetic control and affecting ventricular excitabilityand contractility. This leads to a reduction in arrhythmia potential.

Advantageously, the effects of this approach on other cardiac functionis at a minimum. Furthermore, as soon as the electrical signals areremoved, the block ceases and the baseline cardiac function in theanimal model resumes.

The electrical signals can be delivered in the form of DC or KHFAC. Inthese studies DC was more effective in producing block with a much loweronset effect. KHFAC, which in contrast produces a high onset effect.Increasing current output was able to produce substantially greater DCblock. For sympathetic control, the graded conduction block induced byKHFAC or CBDCC is reversible and scalable. Owing to the KHFAC onsetresponse, CBDCC may be the preferred methodology for arrhythmiamanagement, although there are ways to minimize the onset response.

Finally, in addition to dogs, pig studies revealed that the sameefficacy of block was obtained when KHFAC was applied to T1-T2sympathetic ganglia (when T3 was stimulated). The T1-T2 segment of theparavertebral chain is a principal nexus point for modulation ofsympathetic projections to the heart.

This suggests that the invention could be put into practice at the verylocation that surgeons currently perform denervation of T1-T4sympathetic ganglia.

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1.-59. (canceled)
 60. A device for reversibly modulating neural activityof a subject's cardiac-related sympathetic nerve in the extracardiacintrathoracic neural circuit, the device comprising: at least onetransducer suitable for placement on or around the cardiac-relatedsympathetic nerve, and a signal generator for generating a signal to beapplied to the cardiac-related sympathetic nerve via the at least onetransducer such that the signal reversibly modulates the neural activityof the cardiac-related sympathetic nerve to produce a physiologicalresponse in the subject, wherein the physiological response is adecrease in chronotropic, dromotropic, lusitropic and/or inotropicevoked responses.
 61. The device of claim 60, wherein the at least onetransducer is at least one electrode, and the signal generator is avoltage or current source configured to generate an electrical signal tobe applied to the cardiac-related sympathetic nerve via the at least oneelectrode, and wherein the electrical signal is a kilohertz frequencyalternating current (KHFAC) signal, a charge balanced direct currentcarousel (CBDCC) signal, or a hybrid thereof.
 62. The device of claim60, wherein the cardiac-related sympathetic nerve is modulated, at asite along the paravertebral chain between stellate ganglion and T4ganglion.
 63. The device of claim 60, wherein the cardiac-relatedsympathetic nerve is inhibited, unilaterally or bilaterally.
 64. Thedevice of claim 62, wherein the modulation is inhibition of neuralactivity, and is a full block or a partial block.
 65. The device ofclaim 60, wherein the at least one transducer is in signaling contactwith the cardiac-related sympathetic nerve.
 66. The device of claim 65,wherein the at least one transducer is at least one electrode, and thesignal generator is a voltage or current source configured to generatean electrical signal to be applied to the cardiac-related sympatheticnerve via the at least one electrode.
 67. The device of claim 66,wherein the electrical signal is a KHFAC signal or a DC signal.
 68. Thedevice of claim 67, wherein the electrical signal comprises a DC rampand a KHFAC waveform that commences during the DC ramp.
 69. The deviceof claim 68, wherein the electrical signal comprises, sequentially, a DCramp followed by a plateau and charge-balancing; a first AC waveform,wherein the amplitude of the waveform increases during the period thewaveform is applied; and a second AC waveform having a lower frequencyand/or lower amplitude than the first waveform.
 70. The device of claim67, wherein the electrical signal is a KHFAC signal having a frequencybetween 2 kHz and 30 kHz.
 71. The device of claim 67, wherein theelectrical signal is a charge-balanced DC signal comprising a cathodicpulse and an anodic pulse, the current of the cathodic pulse beingbetween 0.1 mA and 10 mA.
 72. The device of claim 71, wherein theelectrode is a carousel electrode comprising a plurality of electrodecontacts, and wherein the signal generator is configured to apply asignal to each of the plurality of electrode contacts in a repeatingcycle.
 73. The device of claim 72, wherein each electrode contact iscoupled to its own current source, and wherein the signal generator isconfigured to vary the amplitude of the current applied to each of theplurality of electrode contacts independently of the other electrodecontacts.
 74. The device of claim 61, further comprising a detectionsubsystem for detecting electrical activity of the heart, the detectionsubsystem comprising one or more electrical sensors for attachment tothe heart, and upon detection of electrical activity of the heartindicative of cardiac dysfunction or abnormal heart rhythm, causing theelectrical signal to be applied to the cardiac-related sympathetic nervevia the at least one electrode.
 75. The device of claim 60, wherein thesignal generator is configured to apply the electrical signalperiodically.
 76. The device of claim 75, wherein the generator isconfigured to apply the signal in an on-off pattern.
 77. A method oftreating cardiac dysfunction in a subject, comprising: (i) implanting inthe subject a device of claim 1; (ii) positioning the transducer of thedevice or system in signaling contact with the cardiac-relatedsympathetic nerve in the extracardiac intrathoracic neural circuit inthe subject; and optionally (iii) activating the device or system. 78.The method of claim 77, wherein the method is for treating heartfailure, myocardial infarction and cardiac arrhythmias.
 79. The methodof claim 77, wherein the method is for treating or preventingventricular arrhythmia.